Peer-reviewed journal articles
2024
[206]
P. P. Adhikary, T. Idowu, Z. Tan, C. Hoang, S. Shanta, M. Dumbani, L. Mappalakayil, B. Awasthi, M. Bermudez, J. Weiner, D. Beule, G. Wolber, B. D. G. Page, and S. Hedtrich. Disrupting TSLP–TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases, EMBO Molecular Medicine, :1-27-27, 2024.
Links:
[doi:10.1038/s44321-024-00085-3]
[show BibTeX]
[show abstract]
x
@article{RN351,
author = {Adhikary, Partho Protim and Idowu,
Temilolu and Tan, Zheng and Hoang,
Christopher and Shanta, Selina and
Dumbani, Malti and Mappalakayil, Leah and
Awasthi, Bhuwan and Bermudez, Marcel and
Weiner, January and Beule, Dieter and
Wolber, Gerhard and Page, Brent D. G. and
Hedtrich, Sarah},
title = {Disrupting TSLP–TSLP receptor
interactions via putative small molecule
inhibitors yields a novel and efficient
treatment option for atopic diseases},
journal = {EMBO Molecular Medicine},
pages = {1-27-27},
abstract = {AbstractThymic stromal lymphopoietin
(TSLP) is a key player in atopic diseases,
which has sparked great interest in
therapeutically targeting TSLP. Yet, no
small-molecule TSLP inhibitors exist due
to the challenges of disrupting the
protein?protein interaction between TSLP
and its receptor. Here, we report the
development of small-molecule TSLP
receptor inhibitors using virtual
screening and docking of 1,000,000
compounds followed by iterative chemical
synthesis. BP79 emerged as our lead
compound that effectively abrogates
TSLP-triggered cytokines at low micromolar
concentrations. For in-depth analysis, we
developed a human atopic disease drug
discovery platform using multi-organ
chips. Here, topical application of BP79
onto atopic skin models that were
co-cultivated with lung models and Th2
cells effectively suppressed immune cell
infiltration and IL-13, IL-4, TSLP, and
periostin secretion, while upregulating
skin barrier proteins. RNA-Seq analysis
corroborate these findings and indicate
protective downstream effects on the
lungs. To the best of our knowledge, this
represents the first report of a potent
putative small molecule TSLPR inhibitor
which has the potential to expand the
therapeutic and preventive options in
atopic diseases.},
ISSN = {1757-4676},
DOI = {10.1038/s44321-024-00085-3},
url = {https://doi.org/10.1038/s44321-024-00085-3},
year = {2024},
type = {Journal Article}
}
x
Disrupting TSLP–TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases
AbstractThymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein?protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases.
R. A. Ashraf, S. Liu, C. A. Wolf, G. Wolber, and M. Bureik. Identification of new substrates and inhibitors of human CYP2A7, Molecules, 29(10):2191, 2024.
Links:
[doi:10.3390/molecules29102191]
[show BibTeX]
[show abstract]
x
@article{RN350,
author = {Ashraf, R. A. and Liu, S. and Wolf, C. A.
and Wolber, G. and Bureik, M.},
title = {Identification of new substrates and
inhibitors of human CYP2A7},
journal = {Molecules},
volume = {29},
number = {10},
pages = {2191},
note = {Rz6p0 Times Cited:0 Cited References
Count:39},
abstract = {CYP2A7 is one of the most understudied
human cytochrome P450 enzymes and its
contributions to either drug metabolism or
endogenous biosynthesis pathways are not
understood, as its only known enzymatic
activities are the conversions of two
proluciferin probe substrates. In
addition, the CYP2A7 gene contains four
single-nucleotide polymorphisms (SNPs)
that cause missense mutations and have
minor allele frequencies (MAFs) above 0.5.
This means that the resulting amino acid
changes occur in the majority of humans.
In a previous study, we employed the
reference standard sequence (called
CYP2A7*1 in P450 nomenclature). For the
present study, we created another CYP2A7
sequence that contains all four amino acid
changes (Cys311, Glu169, Gly479, and
Arg274) and labeled it CYP2A7-WT. Thus, it
was the aim of this study to identify new
substrates and inhibitors of CYP2A7 and to
compare the properties of CYP2A7-WT with
CYP2A7*1. We found several new
proluciferin probe substrates for both
enzyme variants (we also performed in
silico studies to understand the activity
difference between CYP2A7-WT and CYP2A7*1
on specific substrates), and we show that
while they do not act on the standard
CYP2A6 substrates nicotine, coumarin, or
7-ethoxycoumarin, both can hydroxylate
diclofenac (as can CYP2A6). Moreover, we
found ketoconazole, 1-benzylimidazole, and
letrozole to be CYP2A7 inhibitors.},
DOI = {10.3390/molecules29102191},
url = {Go to ISI://WOS:001231521200001},
year = {2024},
type = {Journal Article}
}
x
Identification of new substrates and inhibitors of human CYP2A7
CYP2A7 is one of the most understudied human cytochrome P450 enzymes and its contributions to either drug metabolism or endogenous biosynthesis pathways are not understood, as its only known enzymatic activities are the conversions of two proluciferin probe substrates. In addition, the CYP2A7 gene contains four single-nucleotide polymorphisms (SNPs) that cause missense mutations and have minor allele frequencies (MAFs) above 0.5. This means that the resulting amino acid changes occur in the majority of humans. In a previous study, we employed the reference standard sequence (called CYP2A7*1 in P450 nomenclature). For the present study, we created another CYP2A7 sequence that contains all four amino acid changes (Cys311, Glu169, Gly479, and Arg274) and labeled it CYP2A7-WT. Thus, it was the aim of this study to identify new substrates and inhibitors of CYP2A7 and to compare the properties of CYP2A7-WT with CYP2A7*1. We found several new proluciferin probe substrates for both enzyme variants (we also performed in silico studies to understand the activity difference between CYP2A7-WT and CYP2A7*1 on specific substrates), and we show that while they do not act on the standard CYP2A6 substrates nicotine, coumarin, or 7-ethoxycoumarin, both can hydroxylate diclofenac (as can CYP2A6). Moreover, we found ketoconazole, 1-benzylimidazole, and letrozole to be CYP2A7 inhibitors.
U. B. A. Aziz, A. Saoud, M. Bermudez, M. Mieth, A. Atef, T. Rudolf, C. Arkona, T. Trenkner, C. Böttcher, K. Ludwig, A. Hoelzemer, A. C. Hocke, G. Wolber, and J. Rademann. Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins, Nat Commun, 15(1):3537, 2024.
Links:
[doi:10.1038/s41467-024-47741-3]
[show BibTeX]
[show abstract]
x
@article{RN349,
author = {Aziz, Umer Bin Abdul and Saoud, Ali and
Bermudez, Marcel and Mieth, Maren and
Atef, Amira and Rudolf, Thomas and Arkona,
Christoph and Trenkner, Timo and
Böttcher, Christoph and Ludwig, Kai and
Hoelzemer, Angelique and Hocke, Andreas C.
and Wolber, Gerhard and Rademann, Jörg},
title = {Targeted small molecule inhibitors
blocking the cytolytic effects of
pneumolysin and homologous toxins},
journal = {Nature Communications},
volume = {15},
number = {1},
pages = {3537},
abstract = {Pneumolysin (PLY) is a
cholesterol-dependent cytolysin (CDC) from
Streptococcus pneumoniae, the main cause
for bacterial pneumonia. Liberation of PLY
during infection leads to compromised
immune system and cytolytic cell death.
Here, we report discovery, development,
and validation of targeted small molecule
inhibitors of PLY (pore-blockers, PB).
PB-1 is a virtual screening hit inhibiting
PLY-mediated hemolysis. Structural
optimization provides PB-2 with improved
efficacy. Cryo-electron tomography reveals
that PB-2 blocks PLY-binding to
cholesterol-containing membranes and
subsequent pore formation.
Scaffold-hopping delivers PB-3 with
superior chemical stability and
solubility. PB-3, formed in a
protein-templated reaction, binds to
Cys428 adjacent to the cholesterol
recognition domain of PLY with a KD of
256 nM and a residence time of 2000 s.
It acts as anti-virulence factor
preventing human lung epithelial cells
from PLY-mediated cytolysis and cell death
during infection with Streptococcus
pneumoniae and is active against the
homologous Cys-containing CDC
perfringolysin (PFO) as well.},
ISSN = {2041-1723},
DOI = {10.1038/s41467-024-47741-3},
url = {https://doi.org/10.1038/s41467-024-47741-3
https://www.nature.com/articles/s41467-024-47741-3.pdf},
year = {2024},
type = {Journal Article}
}
x
Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins
Pneumolysin (PLY) is a cholesterol-dependent cytolysin (CDC) from Streptococcus pneumoniae, the main cause for bacterial pneumonia. Liberation of PLY during infection leads to compromised immune system and cytolytic cell death. Here, we report discovery, development, and validation of targeted small molecule inhibitors of PLY (pore-blockers, PB). PB-1 is a virtual screening hit inhibiting PLY-mediated hemolysis. Structural optimization provides PB-2 with improved efficacy. Cryo-electron tomography reveals that PB-2 blocks PLY-binding to cholesterol-containing membranes and subsequent pore formation. Scaffold-hopping delivers PB-3 with superior chemical stability and solubility. PB-3, formed in a protein-templated reaction, binds to Cys428 adjacent to the cholesterol recognition domain of PLY with a KD of 256 nM and a residence time of 2000 s. It acts as anti-virulence factor preventing human lung epithelial cells from PLY-mediated cytolysis and cell death during infection with Streptococcus pneumoniae and is active against the homologous Cys-containing CDC perfringolysin (PFO) as well.
N. Fuchs, L. Calvo-Barreiro, V. Talagayev, S. Pach, G. Wolber, and M. T. Gabr. From Virtual Screens to Cellular Target Engagement: New Small Molecule Ligands for the Immune Checkpoint LAG-3, ACS Medicinal Chemistry Letters, 15(11):1884-1890, 2024.
Links:
[doi:10.1021/acsmedchemlett.4c00350]
[show BibTeX]
[show abstract]
x
@article{RN354,
author = {Fuchs, Natalie and Calvo-Barreiro, Laura
and Talagayev, Valerij and Pach, Szymon
and Wolber, Gerhard and Gabr, Moustafa
T.},
title = {From Virtual Screens to Cellular Target
Engagement: New Small Molecule Ligands for
the Immune Checkpoint LAG-3},
journal = {ACS Medicinal Chemistry Letters},
volume = {15},
number = {11},
pages = {1884-1890},
note = {doi: 10.1021/acsmedchemlett.4c00350},
abstract = {Herein, we performed a virtual screening
study to discover new scaffolds for small
molecule-based ligands of the immune
checkpoint lymphocyte-activation gene 3
(LAG-3). Molecular dynamics (MD)
simulations using the LAG-3 structure
revealed two putative binding sites for
small molecules: the antibody interface
and the lipophilic canyon. A 3D
pharmacophore screening resulted in the
identification of potential ligands for
these binding sites and afforded a library
of 25 compounds. We then evaluated the
screening hits for LAG-3 binding via
microscale thermophoresis (MST) and
surface plasmon resonance (SPR). Our
biophysical screening identified two
binders with KD values in the low
micromolar range, compounds 3 (antibody
interface) and 25 (lipophilic canyon).
Furthermore, we investigated the ability
of LAG-3 hits to engage LAG-3 on a
cellular level using a cellular thermal
shift assay (CETSA). In summary, compound
3 shows potential as a lead but is not yet
a development candidate.},
DOI = {10.1021/acsmedchemlett.4c00350},
url = {https://doi.org/10.1021/acsmedchemlett.4c00350},
year = {2024},
type = {Journal Article}
}
x
From Virtual Screens to Cellular Target Engagement: New Small Molecule Ligands for the Immune Checkpoint LAG-3
Herein, we performed a virtual screening study to discover new scaffolds for small molecule-based ligands of the immune checkpoint lymphocyte-activation gene 3 (LAG-3). Molecular dynamics (MD) simulations using the LAG-3 structure revealed two putative binding sites for small molecules: the antibody interface and the lipophilic canyon. A 3D pharmacophore screening resulted in the identification of potential ligands for these binding sites and afforded a library of 25 compounds. We then evaluated the screening hits for LAG-3 binding via microscale thermophoresis (MST) and surface plasmon resonance (SPR). Our biophysical screening identified two binders with KD values in the low micromolar range, compounds 3 (antibody interface) and 25 (lipophilic canyon). Furthermore, we investigated the ability of LAG-3 hits to engage LAG-3 on a cellular level using a cellular thermal shift assay (CETSA). In summary, compound 3 shows potential as a lead but is not yet a development candidate.
E. Koçak Aslan, K. Lam, C. Dengiz, K. Denzinger, I. Y. Dicle Erdamar, S. Huang, G. W. Zamponi, G. Wolber, and M. G. Gunduz. Synthesis, molecular modeling, DFT studies, and EPR analysis of 1,4-dihydropyridines as potential calcium channel blockers, J Mol Struct, 1307:137983, 2024.
Links:
[doi:10.1016/j.molstruc.2024.137983]
[show BibTeX]
[show abstract]
x
@article{RN348,
author = {Koçak Aslan, Ebru and Lam, Kevin and
Dengiz, Cagatay and Denzinger, Katrin and
Dicle Erdamar, Isık Yesim and Huang, Sun
and Zamponi, Gerald W. and Wolber, Gerhard
and Gunduz, Miyase Gozde},
title = {Synthesis, molecular modeling, DFT
studies, and EPR analysis of
1,4-dihydropyridines as potential calcium
channel blockers},
journal = {Journal of Molecular Structure},
volume = {1307},
pages = {137983},
abstract = {1,4-Dihydropyridines (DHPs) are widely
recognized as a highly effective class of
L-type calcium channel blockers that offer
significant therapeutic potential in
managing cardiovascular conditions.
Furthermore, their ability to target other
types of calcium channels makes DHPs
attractive candidates for therapeutic
applications in neurological and
psychiatric disorders. Close examination
of the chemical structures of approved
DHP-based antihypertensive drugs with a
history of over forty years in the market
reveals that the C-4 position is the least
altered part of this privileged ring
system. In the present study, we focused
on this position and synthesized two novel
compounds (DB1 and DB2) by carrying out
chemical modifications on suitable
positions of the main scaffold of DA1
(isobutyl
4-(benzo[d][1,3]dioxol-5-yl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate)
that was previously identified as a
DHP-based effective and selective
inhibitor of T-type (Cav3.2) over L-type
(Cav1.2) calcium channel. Based on
whole-cell patch-clamp analysis on Cav1.2
and Cav3.2, DB1 with bromine group on the
benzodioxole ring appeared to be a more
effective and selective inhibitor of
Cav3.2 compared to DB2 with nitro at the
same locus. Molecular docking and
molecular dynamics (MD) simulations were
performed to investigate the binding mode
of both DB1 isomers to Cav3.2.
Furthermore, density functional theory
(DFT) methods were employed to obtain
information regarding the stability of the
molecules by computing various parameters,
such as electric dipole moment, band gap,
electronegativity, and global chemical
hardness-softness, related to their
charge-transfer characteristics. According
to DFT studies, DB1 also appeared to be
chemically more stable than DB2. Finally,
ionizing radiation-induced free radicals
of gamma-irradiated DB1 and DB2 in powder
form were examined utilizing the electron
paramagnetic resonance (EPR) technique and
the obtained data demonstrated that
radiation sterilization is suitable for
the dosage forms including DB1 and DB2.},
ISSN = {0022-2860},
DOI = {10.1016/j.molstruc.2024.137983},
url = {https://www.sciencedirect.com/science/article/pii/S0022286024005052
https://www.sciencedirect.com/science/article/pii/S0022286024005052?via%3Dihub},
year = {2024},
type = {Journal Article}
}
x
Synthesis, molecular modeling, DFT studies, and EPR analysis of 1,4-dihydropyridines as potential calcium channel blockers
1,4-Dihydropyridines (DHPs) are widely recognized as a highly effective class of L-type calcium channel blockers that offer significant therapeutic potential in managing cardiovascular conditions. Furthermore, their ability to target other types of calcium channels makes DHPs attractive candidates for therapeutic applications in neurological and psychiatric disorders. Close examination of the chemical structures of approved DHP-based antihypertensive drugs with a history of over forty years in the market reveals that the C-4 position is the least altered part of this privileged ring system. In the present study, we focused on this position and synthesized two novel compounds (DB1 and DB2) by carrying out chemical modifications on suitable positions of the main scaffold of DA1 (isobutyl 4-(benzo[d][1,3]dioxol-5-yl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate) that was previously identified as a DHP-based effective and selective inhibitor of T-type (Cav3.2) over L-type (Cav1.2) calcium channel. Based on whole-cell patch-clamp analysis on Cav1.2 and Cav3.2, DB1 with bromine group on the benzodioxole ring appeared to be a more effective and selective inhibitor of Cav3.2 compared to DB2 with nitro at the same locus. Molecular docking and molecular dynamics (MD) simulations were performed to investigate the binding mode of both DB1 isomers to Cav3.2. Furthermore, density functional theory (DFT) methods were employed to obtain information regarding the stability of the molecules by computing various parameters, such as electric dipole moment, band gap, electronegativity, and global chemical hardness-softness, related to their charge-transfer characteristics. According to DFT studies, DB1 also appeared to be chemically more stable than DB2. Finally, ionizing radiation-induced free radicals of gamma-irradiated DB1 and DB2 in powder form were examined utilizing the electron paramagnetic resonance (EPR) technique and the obtained data demonstrated that radiation sterilization is suitable for the dosage forms including DB1 and DB2.
F. Li, S. Ackloo, C. H. Arrowsmith, F. Ban, C. J. Barden, H. Beck, J. Beránek, F. Berenger, A. Bolotokova, G. Bret, M. Breznik, E. Carosati, I. Chau, Y. Chen, A. Cherkasov, D. D. Corte, K. Denzinger, A. Dong, S. Draga, I. Dunn, K. Edfeldt, A. Edwards, M. Eguida, P. Eisenhuth, L. Friedrich, A. Fuerll, S. S. Gardiner, F. Gentile, P. Ghiabi, E. Gibson, M. Glavatskikh, C. Gorgulla, J. Guenther, A. Gunnarsson, F. Gusev, E. Gutkin, L. Halabelian, R. J. Harding, A. Hillisch, L. Hoffer, A. Hogner, S. Houliston, J. J. Irwin, O. Isayev, A. Ivanova, C. Jacquemard, A. J. Jarrett, J. H. Jensen, D. Kireev, J. Kleber, S. B. Koby, D. Koes, A. Kumar, M. G. Kurnikova, A. Kutlushina, U. Lessel, F. Liessmann, S. Liu, W. Lu, J. Meiler, A. Mettu, G. Minibaeva, R. Moretti, C. J. Morris, C. Narangoda, T. Noonan, L. Obendorf, S. Pach, A. Pandit, S. Perveen, G. Poda, P. Polishchuk, K. Puls, V. Pütter, D. Rognan, D. Roskams-Edris, C. Schindler, F. Sindt, V. Spiwok, C. Steinmann, R. L. Stevens, V. Talagayev, D. Tingey, O. Vu, W. P. Walters, X. Wang, Z. Wang, G. Wolber, C. A. Wolf, L. Wortmann, H. Zeng, C. A. Zepeda, K. Y. J. Zhang, J. Zhang, S. Zheng, and M. Schapira. CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson’s Disease Associated Protein, J Chem Inf Model, 64(22):8521-8536, 2024.
Links:
[doi:10.1021/acs.jcim.4c01267]
[show BibTeX]
[show abstract]
x
@article{RN352,
author = {Li, Fengling and Ackloo, Suzanne and
Arrowsmith, Cheryl H. and Ban, Fuqiang and
Barden, Christopher J. and Beck, Hartmut
and Beránek, Jan and Berenger, Francois
and Bolotokova, Albina and Bret, Guillaume
and Breznik, Marko and Carosati, Emanuele
and Chau, Irene and Chen, Yu and
Cherkasov, Artem and Corte, Dennis Della
and Denzinger, Katrin and Dong, Aiping and
Draga, Sorin and Dunn, Ian and Edfeldt,
Kristina and Edwards, Aled and Eguida,
Merveille and Eisenhuth, Paul and
Friedrich, Lukas and Fuerll, Alexander and
Gardiner, Spencer S. and Gentile,
Francesco and Ghiabi, Pegah and Gibson,
Elisa and Glavatskikh, Marta and Gorgulla,
Christoph and Guenther, Judith and
Gunnarsson, Anders and Gusev, Filipp and
Gutkin, Evgeny and Halabelian, Levon and
Harding, Rachel J. and Hillisch, Alexander
and Hoffer, Laurent and Hogner, Anders and
Houliston, Scott and Irwin, John J. and
Isayev, Olexandr and Ivanova, Aleksandra
and Jacquemard, Celien and Jarrett, Austin
J. and Jensen, Jan H. and Kireev, Dmitri
and Kleber, Julian and Koby, S. Benjamin
and Koes, David and Kumar, Ashutosh and
Kurnikova, Maria G. and Kutlushina, Alina
and Lessel, Uta and Liessmann, Fabian and
Liu, Sijie and Lu, Wei and Meiler, Jens
and Mettu, Akhila and Minibaeva, Guzel and
Moretti, Rocco and Morris, Connor J. and
Narangoda, Chamali and Noonan, Theresa and
Obendorf, Leon and Pach, Szymon and
Pandit, Amit and Perveen, Sumera and Poda,
Gennady and Polishchuk, Pavel and Puls,
Kristina and Pütter, Vera and Rognan,
Didier and Roskams-Edris, Dylan and
Schindler, Christina and Sindt, François
and Spiwok, Vojtěch and Steinmann, Casper
and Stevens, Rick L. and Talagayev,
Valerij and Tingey, Damon and Vu, Oanh and
Walters, W. Patrick and Wang, Xiaowen and
Wang, Zhenyu and Wolber, Gerhard and Wolf,
Clemens Alexander and Wortmann, Lars and
Zeng, Hong and Zepeda, Carlos A. and
Zhang, Kam Y. J. and Zhang, Jixian and
Zheng, Shuangjia and Schapira, Matthieu},
title = {CACHE Challenge #1: Targeting the WDR
Domain of LRRK2, A Parkinson’s Disease
Associated Protein},
journal = {Journal of Chemical Information and
Modeling},
volume = {64},
number = {22},
pages = {8521-8536},
note = {doi: 10.1021/acs.jcim.4c01267},
abstract = {The CACHE challenges are a series of
prospective benchmarking exercises to
evaluate progress in the field of
computational hit-finding. Here we report
the results of the inaugural CACHE
challenge in which 23 computational teams
each selected up to 100 commercially
available compounds that they predicted
would bind to the WDR domain of the
Parkinson’s disease target LRRK2, a
domain with no known ligand and only an
apo structure in the PDB. The lack of
known binding data and presumably low
druggability of the target is a challenge
to computational hit finding methods. Of
the 1955 molecules predicted by
participants in Round 1 of the challenge,
73 were found to bind to LRRK2 in an SPR
assay with a KD lower than 150 μM. These
73 molecules were advanced to the Round 2
hit expansion phase, where computational
teams each selected up to 50 analogs.
Binding was observed in two orthogonal
assays for seven chemically diverse
series, with affinities ranging from 18 to
140 μM. The seven successful
computational workflows varied in their
screening strategies and techniques. Three
used molecular dynamics to produce a
conformational ensemble of the targeted
site, three included a fragment docking
step, three implemented a generative
design strategy and five used one or more
deep learning steps. CACHE #1 reflects a
highly exploratory phase in computational
drug design where participants adopted
strikingly diverging screening strategies.
Machine learning-accelerated methods
achieved similar results to brute force
(e.g., exhaustive) docking.
First-in-class, experimentally confirmed
compounds were rare and weakly potent,
indicating that recent advances are not
sufficient to effectively address
challenging targets.},
ISSN = {1549-9596},
DOI = {10.1021/acs.jcim.4c01267},
url = {https://doi.org/10.1021/acs.jcim.4c01267},
year = {2024},
type = {Journal Article}
}
x
CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson’s Disease Associated Protein
The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson’s disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Of the 1955 molecules predicted by participants in Round 1 of the challenge, 73 were found to bind to LRRK2 in an SPR assay with a KD lower than 150 μM. These 73 molecules were advanced to the Round 2 hit expansion phase, where computational teams each selected up to 50 analogs. Binding was observed in two orthogonal assays for seven chemically diverse series, with affinities ranging from 18 to 140 μM. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants adopted strikingly diverging screening strategies. Machine learning-accelerated methods achieved similar results to brute force (e.g., exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.
K. Puls, A. Olivé-Marti, S. Hongnak, D. Lamp, M. Spetea, and G. Wolber. Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening, J Med Chem, 67(16):13788-13801, 2024.
Links:
[doi:10.1021/acs.jmedchem.4c00590]
[show BibTeX]
[show abstract]
x
@article{RN355,
author = {Puls, Kristina and Olivé-Marti,
Aina-Leonor and Hongnak, Siriwat and Lamp,
David and Spetea, Mariana and Wolber,
Gerhard},
title = {Discovery of Novel, Selective, and
Nonbasic Agonists for the Kappa-Opioid
Receptor Determined by Salvinorin A-Based
Virtual Screening},
journal = {Journal of Medicinal Chemistry},
volume = {67},
number = {16},
pages = {13788-13801},
note = {doi: 10.1021/acs.jmedchem.4c00590},
abstract = {Modulating the kappa-opioid receptor
(KOR) is a promising strategy for treating
various human diseases. KOR agonists show
potential for treating pain, pruritus, and
epilepsy, while KOR antagonists show
potential for treating depression,
anxiety, and addiction. The diterpenoid
Salvinorin A (SalA), a secondary
metabolite of Salvia divinorum, is a
potent and selective KOR agonist. Unlike
typical opioids, SalA lacks a basic
nitrogen, which encouraged us to search
for nonbasic KOR ligands. Through
structure-based virtual screening using 3D
pharmacophore models based on the binding
mode of SalA, we identified novel,
nonbasic, potent, and selective KOR
agonists. In vitro studies confirmed two
virtual hits, SalA-VS-07 and SalA-VS-08,
as highly selective for the KOR and
showing G protein-biased KOR agonist
activity. Both KOR ligands share a novel
spiro-moiety and a nonbasic scaffold. Our
findings provide novel starting points for
developing therapeutics aimed at treating
pain and other conditions in which KOR is
a central player.},
ISSN = {0022-2623},
DOI = {10.1021/acs.jmedchem.4c00590},
url = {https://doi.org/10.1021/acs.jmedchem.4c00590
https://pmc.ncbi.nlm.nih.gov/articles/PMC11345774/pdf/jm4c00590.pdf},
year = {2024},
type = {Journal Article}
}
x
Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening
Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating various human diseases. KOR agonists show potential for treating pain, pruritus, and epilepsy, while KOR antagonists show potential for treating depression, anxiety, and addiction. The diterpenoid Salvinorin A (SalA), a secondary metabolite of Salvia divinorum, is a potent and selective KOR agonist. Unlike typical opioids, SalA lacks a basic nitrogen, which encouraged us to search for nonbasic KOR ligands. Through structure-based virtual screening using 3D pharmacophore models based on the binding mode of SalA, we identified novel, nonbasic, potent, and selective KOR agonists. In vitro studies confirmed two virtual hits, SalA-VS-07 and SalA-VS-08, as highly selective for the KOR and showing G protein-biased KOR agonist activity. Both KOR ligands share a novel spiro-moiety and a nonbasic scaffold. Our findings provide novel starting points for developing therapeutics aimed at treating pain and other conditions in which KOR is a central player.
L. L. Sallandt, C. A. Wolf, S. Schuster, H. Enke, D. Enke, G. Wolber, and T. H. J. Niedermeyer. Derivatization of Microcystins Can Increase Target Inhibition while Reducing Cellular Uptake, J Nat Prod, :e-pub ahead of print, 2024.
Links:
[doi:10.1021/acs.jnatprod.4c00688]
[show BibTeX]
[show abstract]
x
@article{RN353,
author = {Sallandt, Laura L. and Wolf, Clemens A.
and Schuster, Sabine and Enke, Heike and
Enke, Dan and Wolber, Gerhard and
Niedermeyer, Timo H. J.},
title = {Derivatization of Microcystins Can
Increase Target Inhibition while Reducing
Cellular Uptake},
journal = {Journal of Natural Products},
pages = {e-pub ahead of print},
note = {doi: 10.1021/acs.jnatprod.4c00688},
abstract = {Microcystins, a large family of
nonribosomal cyclic heptapeptides known
for their hepatotoxicity, are among the
best-studied cyanobacterial toxins.
Recently, they have been discussed as
leads for the development of anticancer
drug substances. Their main mode-of-action
is inhibition of the eukaryotic
serine/threonine protein phosphatases 1
and 2A. Unlike many cytotoxins that can
cross cell membranes by passive diffusion,
microcystins depend on active uptake via
organic anion transporting polypeptides
1B1 or 1B3. Both phosphatase inhibition
and transportability strongly depend on
the structure of the individual
microcystin. Here, we present how chemical
modification of positions 2 and 4 of the
microcystin core structure can alter these
two properties. Aiming to reduce
transportability and increase phosphatase
inhibition, we used pharmacophore modeling
to investigate the phosphatase inhibition
potential of microcystins derivatized with
small molecules containing a variety of
functional groups. The respective
derivatives were synthesized using click
chemistry. We discovered that some
derivatized microcystins can address a yet
undescribed subpocket of the protein
phosphatase 1. The derivatized
microcystins were tested for phosphatase 1
inhibition and cytotoxicity on
transporter-expressing cell lines,
revealing that target inhibition and
transportability of microcystins can
independently be influenced by the
physicochemical properties, especially of
the residue located in position 2 of the
microcystin. Derivatization with small
acids or amino acids resulted in
microcystins with a favorable ratio of
inhibition to transportability, making
these derivatives potentially suitable for
drug development.},
ISSN = {0163-3864},
DOI = {10.1021/acs.jnatprod.4c00688},
url = {https://doi.org/10.1021/acs.jnatprod.4c00688},
year = {2024},
type = {Journal Article}
}
x
Derivatization of Microcystins Can Increase Target Inhibition while Reducing Cellular Uptake
Microcystins, a large family of nonribosomal cyclic heptapeptides known for their hepatotoxicity, are among the best-studied cyanobacterial toxins. Recently, they have been discussed as leads for the development of anticancer drug substances. Their main mode-of-action is inhibition of the eukaryotic serine/threonine protein phosphatases 1 and 2A. Unlike many cytotoxins that can cross cell membranes by passive diffusion, microcystins depend on active uptake via organic anion transporting polypeptides 1B1 or 1B3. Both phosphatase inhibition and transportability strongly depend on the structure of the individual microcystin. Here, we present how chemical modification of positions 2 and 4 of the microcystin core structure can alter these two properties. Aiming to reduce transportability and increase phosphatase inhibition, we used pharmacophore modeling to investigate the phosphatase inhibition potential of microcystins derivatized with small molecules containing a variety of functional groups. The respective derivatives were synthesized using click chemistry. We discovered that some derivatized microcystins can address a yet undescribed subpocket of the protein phosphatase 1. The derivatized microcystins were tested for phosphatase 1 inhibition and cytotoxicity on transporter-expressing cell lines, revealing that target inhibition and transportability of microcystins can independently be influenced by the physicochemical properties, especially of the residue located in position 2 of the microcystin. Derivatization with small acids or amino acids resulted in microcystins with a favorable ratio of inhibition to transportability, making these derivatives potentially suitable for drug development.
2023
[198]
S. A. Abdel-Rahman, V. Talagayev, S. Pach, G. Wolber, and M. T. Gabr. Discovery of Small-Molecule TIM-3 Inhibitors for Acute Myeloid Leukemia Using Pharmacophore-Based Virtual Screening, J Med Chem, 66(16):11464-11475, 2023.
Links:
[doi:10.1021/acs.jmedchem.3c00960]
[show BibTeX]
[show abstract]
x
@article{RN339,
author = {Abdel-Rahman, Somaya A. and Talagayev,
Valerij and Pach, Szymon and Wolber,
Gerhard and Gabr, Moustafa T.},
title = {Discovery of Small-Molecule TIM-3
Inhibitors for Acute Myeloid Leukemia
Using Pharmacophore-Based Virtual
Screening},
journal = {Journal of Medicinal Chemistry},
volume = {66},
number = {16},
pages = {11464-11475},
note = {doi: 10.1021/acs.jmedchem.3c00960},
abstract = {T-cell immunoglobulin and mucin domain 3
(TIM-3) is a negative immune checkpoint
that represents a promising target for
cancer immunotherapy. Although encouraging
results have been observed for TIM-3
inhibition in the context of acute myeloid
leukemia (AML), targeting TIM-3 is
currently restricted to monoclonal
antibodies (mAbs). To fill this gap, we
implemented a pharmacophore-based
screening approach to identify
small-molecule TIM-3 inhibitors. Our
approach resulted in the identification of
hit compounds with TIM-3 binding affinity.
Subsequently, we used the
structure–activity relationship (SAR) by
a catalog approach to identify compound
A-41 with submicromolar TIM-3 binding
affinity. Remarkably, A-41 demonstrated
the ability to block TIM-3 interactions
with key ligands and inhibited the
immunosuppressive function of TIM-3 using
an in vitro coculture assay. This work
will pave the way for future drug
discovery efforts aiming at the
development of small-molecule inhibitors
TIM-3 for AML.},
ISSN = {0022-2623},
DOI = {10.1021/acs.jmedchem.3c00960},
url = {https://doi.org/10.1021/acs.jmedchem.3c00960},
year = {2023},
type = {Journal Article}
}
x
Discovery of Small-Molecule TIM-3 Inhibitors for Acute Myeloid Leukemia Using Pharmacophore-Based Virtual Screening
T-cell immunoglobulin and mucin domain 3 (TIM-3) is a negative immune checkpoint that represents a promising target for cancer immunotherapy. Although encouraging results have been observed for TIM-3 inhibition in the context of acute myeloid leukemia (AML), targeting TIM-3 is currently restricted to monoclonal antibodies (mAbs). To fill this gap, we implemented a pharmacophore-based screening approach to identify small-molecule TIM-3 inhibitors. Our approach resulted in the identification of hit compounds with TIM-3 binding affinity. Subsequently, we used the structure–activity relationship (SAR) by a catalog approach to identify compound A-41 with submicromolar TIM-3 binding affinity. Remarkably, A-41 demonstrated the ability to block TIM-3 interactions with key ligands and inhibited the immunosuppressive function of TIM-3 using an in vitro coculture assay. This work will pave the way for future drug discovery efforts aiming at the development of small-molecule inhibitors TIM-3 for AML.
L. Calvo-Barreiro, V. Talagayev, S. Pach, S. A. Abdel-Rahman, G. Wolber, and M. T. Gabr. Discovery of ICOS-Targeted Small Molecules Using Pharmacophore-Based Screening, ChemMedChem, n/a(n/a):e202300305, 2023.
Links:
[doi:https://.org/10.1002/cmdc.202300305]
[show BibTeX]
[show abstract]
x
@article{RN343,
author = {Calvo-Barreiro, Laura and Talagayev,
Valerij and Pach, Szymon and Abdel-Rahman,
Somaya A. and Wolber, Gerhard and Gabr,
Moustafa T.},
title = {Discovery of ICOS-Targeted Small
Molecules Using Pharmacophore-Based
Screening},
journal = {ChemMedChem},
volume = {n/a},
number = {n/a},
pages = {e202300305},
abstract = {Abstract There are currently no small
molecules clinically approved as immune
checkpoint modulators. Besides possessing
oral bioavailability, cell-penetrating
capabilities and enhanced tumor
penetration compared to monoclonal
antibodies (mAbs), small molecules are
amenable to pharmacokinetic optimization,
which allows adopting flexible dosage
regimens that may avoid immune-related
adverse events associated with mAbs. The
interaction of inducible co-stimulator
(ICOS) with its ligand (ICOS-L) plays key
roles in T-cell differentiation and
activation of T-cell to B-cell functions.
This study represents the development and
validation of a virtual screening strategy
to identify small molecules that bind a
novel druggable binding pocket in human
ICOS. We used a lipophilic canyon in the
apo-structure of ICOS and the ICOS/ICOS-L
interface individually as templates for
molecular dynamics simulation to generate
3D pharmacophores subsequently used for
virtual screening campaigns. Our strategy
was successful finding a first-in-class
small molecule ICOS binder (5P, KD
value=108.08±26.76??M) and validating
biophysical screening platforms for
ICOS-targeted small molecules. We
anticipate that future structural
optimization of 5P will result in the
discovery of high affinity chemical
ligands for ICOS.},
ISSN = {1860-7179},
DOI = {https://doi.org/10.1002/cmdc.202300305},
url = {https://doi.org/10.1002/cmdc.202300305
https://chemistry-europe.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cmdc.202300305?download= true},
year = {2023},
type = {Journal Article}
}
x
Discovery of ICOS-Targeted Small Molecules Using Pharmacophore-Based Screening
Abstract There are currently no small molecules clinically approved as immune checkpoint modulators. Besides possessing oral bioavailability, cell-penetrating capabilities and enhanced tumor penetration compared to monoclonal antibodies (mAbs), small molecules are amenable to pharmacokinetic optimization, which allows adopting flexible dosage regimens that may avoid immune-related adverse events associated with mAbs. The interaction of inducible co-stimulator (ICOS) with its ligand (ICOS-L) plays key roles in T-cell differentiation and activation of T-cell to B-cell functions. This study represents the development and validation of a virtual screening strategy to identify small molecules that bind a novel druggable binding pocket in human ICOS. We used a lipophilic canyon in the apo-structure of ICOS and the ICOS/ICOS-L interface individually as templates for molecular dynamics simulation to generate 3D pharmacophores subsequently used for virtual screening campaigns. Our strategy was successful finding a first-in-class small molecule ICOS binder (5P, KD value=108.08±26.76??M) and validating biophysical screening platforms for ICOS-targeted small molecules. We anticipate that future structural optimization of 5P will result in the discovery of high affinity chemical ligands for ICOS.
Y. Jia, B. Schroeder, Y. Pfeifer, C. Fröhlich, L. Deng, C. Arkona, B. Kuropka, J. Sticht, K. Ataka, S. Bergemann, G. Wolber, C. Nitsche, M. Mielke, H. S. Leiros, G. Werner, and J. Rademann. Kinetics, Thermodynamics, and Structural Effects of Quinoline-2-Carboxylates, Zinc-Binding Inhibitors of New Delhi Metallo-β-lactamase-1 Re-sensitizing Multidrug-Resistant Bacteria for Carbapenems, J Med Chem, 66(17):11761-11791, 2023.
Links:
[doi:10.1021/acs.jmedchem.3c00171]
[show BibTeX]
[show abstract]
x
@article{RN337,
author = {Jia, Yuwen and Schroeder, Barbara and
Pfeifer, Yvonne and Fröhlich, Christopher
and Deng, Lihua and Arkona, Christoph and
Kuropka, Benno and Sticht, Jana and Ataka,
Kenichi and Bergemann, Silke and Wolber,
Gerhard and Nitsche, Christoph and Mielke,
Martin and Leiros, Hanna-Kirsti S. and
Werner, Guido and Rademann, Jörg},
title = {Kinetics, Thermodynamics, and Structural
Effects of Quinoline-2-Carboxylates,
Zinc-Binding Inhibitors of New Delhi
Metallo-β-lactamase-1 Re-sensitizing
Multidrug-Resistant Bacteria for
Carbapenems},
journal = {Journal of Medicinal Chemistry},
volume = {66},
number = {17},
pages = {11761-11791},
note = {doi: 10.1021/acs.jmedchem.3c00171},
abstract = {Carbapenem resistance mediated by
metallo-β-lactamases (MBL) such as New
Delhi metallo-β-lactamase-1 (NDM-1) has
become a major factor threatening the
efficacy of essential β-lactam
antibiotics. Starting from hit fragment
dipicolinic acid (DPA), 8-hydroxy- and
8-sulfonamido-quinoline-2-carboxylic acids
were developed as inhibitors of NDM-1 with
highly improved inhibitory activity and
binding affinity. The most active
compounds formed reversibly inactive
ternary protein-inhibitor complexes with
two zinc ions as proven by native protein
mass spectrometry and bio-layer
interferometry. Modification of the NDM-1
structure with remarkable entropic gain
was shown by isothermal titration
calorimetry and NMR spectroscopy of
isotopically labeled protein. The best
compounds were potent inhibitors of NDM-1
and other representative MBL with no or
little inhibition of human zinc-binding
enzymes. These inhibitors significantly
reduced the minimum inhibitory
concentrations (MIC) of meropenem for
multidrug-resistant bacteria recombinantly
expressing blaNDM-1 as well as for several
multidrug-resistant clinical strains at
concentrations non-toxic to human cells.},
ISSN = {0022-2623},
DOI = {10.1021/acs.jmedchem.3c00171},
url = {https://doi.org/10.1021/acs.jmedchem.3c00171},
year = {2023},
type = {Journal Article}
}
x
Kinetics, Thermodynamics, and Structural Effects of Quinoline-2-Carboxylates, Zinc-Binding Inhibitors of New Delhi Metallo-β-lactamase-1 Re-sensitizing Multidrug-Resistant Bacteria for Carbapenems
Carbapenem resistance mediated by metallo-β-lactamases (MBL) such as New Delhi metallo-β-lactamase-1 (NDM-1) has become a major factor threatening the efficacy of essential β-lactam antibiotics. Starting from hit fragment dipicolinic acid (DPA), 8-hydroxy- and 8-sulfonamido-quinoline-2-carboxylic acids were developed as inhibitors of NDM-1 with highly improved inhibitory activity and binding affinity. The most active compounds formed reversibly inactive ternary protein-inhibitor complexes with two zinc ions as proven by native protein mass spectrometry and bio-layer interferometry. Modification of the NDM-1 structure with remarkable entropic gain was shown by isothermal titration calorimetry and NMR spectroscopy of isotopically labeled protein. The best compounds were potent inhibitors of NDM-1 and other representative MBL with no or little inhibition of human zinc-binding enzymes. These inhibitors significantly reduced the minimum inhibitory concentrations (MIC) of meropenem for multidrug-resistant bacteria recombinantly expressing blaNDM-1 as well as for several multidrug-resistant clinical strains at concentrations non-toxic to human cells.
V. Kremling, B. Loll, S. Pach, I. Dahmani, C. Weise, G. Wolber, S. Chiantia, M. C. Wahl, N. Osterrieder, and W. Azab. Crystal structures of glycoprotein D of equine alphaherpesviruses reveal potential binding sites to the entry receptor MHC-I, Frontiers in Microbiology, 14:1197120, 2023.
Links:
[doi:10.3389/fmicb.2023.1197120]
[show BibTeX]
[show abstract]
x
@article{RN335,
author = {Kremling, Viviane and Loll, Bernhard and
Pach, Szymon and Dahmani, Ismail and
Weise, Christoph and Wolber, Gerhard and
Chiantia, Salvatore and Wahl, Markus C.
and Osterrieder, Nikolaus and Azab,
Walid},
title = {Crystal structures of glycoprotein D of
equine alphaherpesviruses reveal potential
binding sites to the entry receptor
MHC-I},
journal = {Frontiers in Microbiology},
volume = {14},
pages = {1197120},
abstract = {Cell entry of most alphaherpesviruses is
mediated by the binding of glycoprotein D
(gD) to different cell surface receptors.
Equine herpesvirus type 1 (EHV-1) and
EHV-4 gDs interact with equine major
histocompatibility complex I (MHC-I) to
initiate entry into equine cells. We have
characterized the gD-MHC-I interaction by
solving the crystal structures of EHV-1
and EHV-4 gDs (gD1, gD4), performing
protein-protein docking simulations,
surface plasmon resonance (SPR) analysis,
and biological assays. The structures of
gD1 and gD4 revealed the existence of a
common V-set immunoglobulin-like
(IgV-like) core comparable to those of
other gD homologs. Molecular modeling
yielded plausible binding hypotheses and
identified key residues (F213 and D261)
that are important for virus binding.
Altering the key residues resulted in
impaired virus growth in cells, which
highlights the important role of these
residues in the gD-MHC-I interaction.
Taken together, our results add to our
understanding of the initial
herpesvirus-cell interactions and will
contribute to the targeted design of
antiviral drugs and vaccine development.},
ISSN = {1664-302X},
DOI = {10.3389/fmicb.2023.1197120},
url = {https://www.frontiersin.org/articles/10.3389/fmicb.2023.1197120},
year = {2023},
type = {Journal Article}
}
x
Crystal structures of glycoprotein D of equine alphaherpesviruses reveal potential binding sites to the entry receptor MHC-I
Cell entry of most alphaherpesviruses is mediated by the binding of glycoprotein D (gD) to different cell surface receptors. Equine herpesvirus type 1 (EHV-1) and EHV-4 gDs interact with equine major histocompatibility complex I (MHC-I) to initiate entry into equine cells. We have characterized the gD-MHC-I interaction by solving the crystal structures of EHV-1 and EHV-4 gDs (gD1, gD4), performing protein-protein docking simulations, surface plasmon resonance (SPR) analysis, and biological assays. The structures of gD1 and gD4 revealed the existence of a common V-set immunoglobulin-like (IgV-like) core comparable to those of other gD homologs. Molecular modeling yielded plausible binding hypotheses and identified key residues (F213 and D261) that are important for virus binding. Altering the key residues resulted in impaired virus growth in cells, which highlights the important role of these residues in the gD-MHC-I interaction. Taken together, our results add to our understanding of the initial herpesvirus-cell interactions and will contribute to the targeted design of antiviral drugs and vaccine development.
R. Maccari, G. Wolber, M. Genovese, G. Sardelli, V. Talagayev, F. Balestri, S. Luti, A. Santi, R. Moschini, A. Del Corso, P. Paoli, and R. Ottana. Designed multiple ligands for the treatment of type 2 diabetes mellitus and its complications: Discovery of (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids active as novel dual-targeted PTP1B/AKR1B1 inhibitors, Eur J Med Chem, 252:115270, 2023.
Links:
[doi:10.1016/j.ejmech.2023.115270]
[show BibTeX]
[show abstract]
x
@article{RN334,
author = {Maccari, Rosanna and Wolber, Gerhard and
Genovese, Massimo and Sardelli, Gemma and
Talagayev, Valerij and Balestri, Francesco
and Luti, Simone and Santi, Alice and
Moschini, Roberta and Del Corso, Antonella
and Paoli, Paolo and Ottana, Rosaria},
title = {Designed multiple ligands for the
treatment of type 2 diabetes mellitus and
its complications: Discovery of
(5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic
acids active as novel dual-targeted
PTP1B/AKR1B1 inhibitors},
journal = {European Journal of Medicinal Chemistry},
volume = {252},
pages = {115270},
abstract = {Type 2 diabetes mellitus (T2DM) is a
serious chronic disease with an alarmingly
growing worldwide prevalence. Current
treatment of T2DM mainly relies on drug
combinations in order to control blood
glucose levels and consequently prevent
the onset of hyperglycaemia-related
complications. The development of
multiple-targeted drugs recently emerged
as an attractive alternative to drug
combinations for the treatment of complex
diseases with multifactorial pathogenesis,
such as T2DM. Protein tyrosine phosphatase
1B (PTP1B) and aldose reductase (AKR1B1)
are two enzymes crucially involved in the
development of T2DM and its chronic
complications and, therefore, dual
inhibitors targeted to both these enzymes
could provide novel agents for the
treatment of this complex pathological
condition. In continuing our search for
dual-targeted PTP1B/AKR1B1 inhibitors, we
designed new
(5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic
acids. Among them,
3-(4-phenylbutoxy)benzylidene derivatives
6f and 7f, endowed with interesting
inhibitory activity against both targets,
proved to control specific cellular
pathways implicated in the development of
T2DM and related complications.},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2023.115270},
url = {https://www.sciencedirect.com/science/article/pii/S0223523423002362},
year = {2023},
type = {Journal Article}
}
x
Designed multiple ligands for the treatment of type 2 diabetes mellitus and its complications: Discovery of (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids active as novel dual-targeted PTP1B/AKR1B1 inhibitors
Type 2 diabetes mellitus (T2DM) is a serious chronic disease with an alarmingly growing worldwide prevalence. Current treatment of T2DM mainly relies on drug combinations in order to control blood glucose levels and consequently prevent the onset of hyperglycaemia-related complications. The development of multiple-targeted drugs recently emerged as an attractive alternative to drug combinations for the treatment of complex diseases with multifactorial pathogenesis, such as T2DM. Protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AKR1B1) are two enzymes crucially involved in the development of T2DM and its chronic complications and, therefore, dual inhibitors targeted to both these enzymes could provide novel agents for the treatment of this complex pathological condition. In continuing our search for dual-targeted PTP1B/AKR1B1 inhibitors, we designed new (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids. Among them, 3-(4-phenylbutoxy)benzylidene derivatives 6f and 7f, endowed with interesting inhibitory activity against both targets, proved to control specific cellular pathways implicated in the development of T2DM and related complications.
K. Puls, and G. Wolber. Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor, Molecules, 28(2):718, 2023.
Links:
[doi:10.3390/molecules28020718]
[show BibTeX]
[show abstract]
x
@article{RN331,
author = {Puls, Kristina and Wolber, Gerhard},
title = {Solving an Old Puzzle: Elucidation and
Evaluation of the Binding Mode of
Salvinorin A at the Kappa Opioid
Receptor},
journal = {Molecules},
volume = {28},
number = {2},
pages = {718},
abstract = {The natural product Salvinorin A (SalA)
was the first nitrogen-lacking agonist
discovered for the opioid receptors and
exhibits high selectivity for the kappa
opioid receptor (KOR) turning SalA into a
promising analgesic to overcome the
current opioid crisis. Since SalA’s
suffers from poor pharmacokinetic
properties, particularly the absence of
gastrointestinal bioavailability, fast
metabolic inactivation, and subsequent
short duration of action, the rational
design of new tailored analogs with
improved clinical usability is highly
desired. Despite being known for decades,
the binding mode of SalA within the KOR
remains elusive as several conflicting
binding modes of SalA were proposed
hindering the rational design of new
analgesics. In this study, we rationally
determined the binding mode of SalA to the
active state KOR by in silico experiments
(docking, molecular dynamics simulations,
dynophores) in the context of all
available mutagenesis studies and
structure-activity relationship (SAR)
data. To the best of our knowledge, this
is the first comprehensive evaluation of
SalA’s binding mode since the
determination of the active state KOR
crystal structure. SalA binds above the
morphinan binding site with its furan
pointing toward the intracellular core
while the C2-acetoxy group is oriented
toward the extracellular loop 2 (ECL2).
SalA is solely stabilized within the
binding pocket by hydrogen bonds
(C210ECL2, Y3127.35, Y3137.36) and
hydrophobic contacts (V1182.63, I1393.33,
I2946.55, I3167.39). With the disruption
of this interaction pattern or the
establishment of additional interactions
within the binding site, we were able to
rationalize the experimental data for
selected analogs. We surmise the
C2-substituent interactions as important
for SalA and its analogs to be
experimentally active, albeit with
moderate frequency within MD simulations
of SalA. We further identified the
non-conserved residues 2.63, 7.35, and
7.36 responsible for the KOR subtype
selectivity of SalA. We are confident that
the elucidation of the SalA binding mode
will promote the understanding of KOR
activation and facilitate the development
of novel analgesics that are urgently
needed.},
ISSN = {1420-3049},
DOI = {10.3390/molecules28020718},
year = {2023},
type = {Journal Article}
}
x
Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor
The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation, and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge, this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing toward the intracellular core while the C2-acetoxy group is oriented toward the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site, we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit with moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and facilitate the development of novel analgesics that are urgently needed.
F. Ricci, K. Schira, L. Khettabi, L. Lombardo, S. Mirabile, R. Gitto, M. Soler-Lopez, J. Scheuermann, G. Wolber, and L. De Luca. Computational methods to analyze and predict the binding mode of inhibitors targeting both human and mushroom tyrosinase, Eur J Med Chem, 260:115771, 2023.
Links:
[doi:10.1016/j.ejmech.2023.115771]
[show BibTeX]
[show abstract]
x
@article{RN338,
author = {Ricci, Federico and Schira, Kristina and
Khettabi, Lyna and Lombardo, Lisa and
Mirabile, Salvatore and Gitto, Rosaria and
Soler-Lopez, Montserrat and Scheuermann,
Jörg and Wolber, Gerhard and De Luca,
Laura},
title = {Computational methods to analyze and
predict the binding mode of inhibitors
targeting both human and mushroom
tyrosinase},
journal = {European Journal of Medicinal Chemistry},
volume = {260},
pages = {115771},
abstract = {Tyrosinase, a copper-containing enzyme
critical in melanin biosynthesis, is a key
drug target for hyperpigmentation and
melanoma in humans. Testing the inhibitory
effects of compounds using tyrosinase from
Agaricus bisporus (AbTYR) has been a
common practice to identify potential
therapeutics from synthetic and natural
sources. However, structural diversity
among human tyrosinase (hTYR) and AbTYR
presents a challenge in developing drugs
that are therapeutically effective. In
this study, we combined retrospective and
computational analyses with experimental
data to provide insights into the
development of new inhibitors targeting
both hTYR and AbTYR. We observed
contrasting effects of Thiamidol™ and
our
4-(4-hydroxyphenyl)piperazin-1-yl-derivative
(6) on both enzymes; based on this
finding, we aimed to investigate their
binding modes in hTYR and AbTYR to
identify residues that significantly
improve affinity. All the information led
to the discovery of compound
[4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone
(MehT-3, 7), which showed comparable
activity on AbTYR (IC50 = 3.52 μM) and
hTYR (IC50 = 5.4 μM). Based on these
achievements we propose the exploitation
of our computational results to provide
relevant structural information for the
development of newer dual-targeting
molecules, which could be preliminarily
tested on AbTYR as a rapid and inexpensive
screening procedure before being tested on
hTYR.},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2023.115771},
url = {https://www.sciencedirect.com/science/article/pii/S0223523423007389
https://www.sciencedirect.com/science/article/pii/S0223523423007389?via%3Dihub},
year = {2023},
type = {Journal Article}
}
x
Computational methods to analyze and predict the binding mode of inhibitors targeting both human and mushroom tyrosinase
Tyrosinase, a copper-containing enzyme critical in melanin biosynthesis, is a key drug target for hyperpigmentation and melanoma in humans. Testing the inhibitory effects of compounds using tyrosinase from Agaricus bisporus (AbTYR) has been a common practice to identify potential therapeutics from synthetic and natural sources. However, structural diversity among human tyrosinase (hTYR) and AbTYR presents a challenge in developing drugs that are therapeutically effective. In this study, we combined retrospective and computational analyses with experimental data to provide insights into the development of new inhibitors targeting both hTYR and AbTYR. We observed contrasting effects of Thiamidol™ and our 4-(4-hydroxyphenyl)piperazin-1-yl-derivative (6) on both enzymes; based on this finding, we aimed to investigate their binding modes in hTYR and AbTYR to identify residues that significantly improve affinity. All the information led to the discovery of compound [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3, 7), which showed comparable activity on AbTYR (IC50 = 3.52 μM) and hTYR (IC50 = 5.4 μM). Based on these achievements we propose the exploitation of our computational results to provide relevant structural information for the development of newer dual-targeting molecules, which could be preliminarily tested on AbTYR as a rapid and inexpensive screening procedure before being tested on hTYR.
Y. Shi, J. Li, C. A. Wolf, S. Liu, S. S. Sharma, G. Wolber, M. Bureik, and B. R. Clark. Expected and Unexpected Products from the Biochemical Oxidation of Bacterial Alkylquinolones with CYP4F11, J Nat Prod, :, 2023.
Links:
[doi:10.1021/acs.jnatprod.3c00689]
[show BibTeX]
[show abstract]
x
@article{RN344,
author = {Shi, Yue and Li, Jianye and Wolf, Clemens
Alexander and Liu, Sijie and Sharma,
Sangeeta S. and Wolber, Gerhard and
Bureik, Matthias and Clark, Benjamin R.},
title = {Expected and Unexpected Products from the
Biochemical Oxidation of Bacterial
Alkylquinolones with CYP4F11},
journal = {Journal of Natural Products},
note = {doi: 10.1021/acs.jnatprod.3c00689},
abstract = {2-Alkylquinolones are a class of
microbial natural products primarily
produced in the Pseudomonas and
Burkholderia genera that play a key role
in modulating quorum sensing. Bacterial
alkylquinolones were synthesized and then
subjected to oxidative biotransformation
using human cytochrome P450 enzyme
CYP4F11, heterologously expressed in the
fission yeast Schizosaccharomyces pombe.
This yielded a range of hydroxylated and
carboxylic acid derivatives which had
undergone ω-oxidation of the 2-alkyl
chain, the structures of which were
determined by analysis of NMR and MS data.
Oxidation efficiency depended on chain
length, with a chain length of eight or
nine carbon atoms proving optimal for high
yields. Homology modeling suggested that
Glu233 was relevant for binding, due to
the formation of a hydrogen bond from the
quinolone nitrogen to Glu233, and in this
position only the longer alkyl chains
could come close enough to the heme moiety
for effective oxidation. In addition to
the direct oxidation products, a number of
esters were also isolated, which was
attributed to the action of endogenous
yeast enzymes on the newly formed
ω-hydroxy-alkylquinolones. ω-Oxidation
of the alkyl chain significantly reduced
the antimicrobial and antibiofilm activity
of the quinolones.},
ISSN = {0163-3864},
DOI = {10.1021/acs.jnatprod.3c00689},
url = {https://doi.org/10.1021/acs.jnatprod.3c00689
https://pubs.acs.org/doi/pdf/10.1021/acs.jnatprod.3c00689},
year = {2023},
type = {Journal Article}
}
x
Expected and Unexpected Products from the Biochemical Oxidation of Bacterial Alkylquinolones with CYP4F11
2-Alkylquinolones are a class of microbial natural products primarily produced in the Pseudomonas and Burkholderia genera that play a key role in modulating quorum sensing. Bacterial alkylquinolones were synthesized and then subjected to oxidative biotransformation using human cytochrome P450 enzyme CYP4F11, heterologously expressed in the fission yeast Schizosaccharomyces pombe. This yielded a range of hydroxylated and carboxylic acid derivatives which had undergone ω-oxidation of the 2-alkyl chain, the structures of which were determined by analysis of NMR and MS data. Oxidation efficiency depended on chain length, with a chain length of eight or nine carbon atoms proving optimal for high yields. Homology modeling suggested that Glu233 was relevant for binding, due to the formation of a hydrogen bond from the quinolone nitrogen to Glu233, and in this position only the longer alkyl chains could come close enough to the heme moiety for effective oxidation. In addition to the direct oxidation products, a number of esters were also isolated, which was attributed to the action of endogenous yeast enzymes on the newly formed ω-hydroxy-alkylquinolones. ω-Oxidation of the alkyl chain significantly reduced the antimicrobial and antibiofilm activity of the quinolones.
Y. Shi, C. A. Wolf, R. Lotfy, S. S. Sharma, A. F. Tesfa, G. Wolber, M. Bureik, and B. R. Clark. Deciphering the biotransformation mechanism of dialkylresorcinols by CYP4F11, Bioorg Chem, 131:106330, 2023.
Links:
[doi:10.1016/j.bioorg.2022.106330]
[show BibTeX]
[show abstract]
x
@article{RN330,
author = {Shi, Yue and Wolf, Clemens A. and Lotfy,
Rowaa and Sharma, Sangeeta S. and Tesfa,
Abel Fekadu and Wolber, Gerhard and
Bureik, Matthias and Clark, Benjamin R.},
title = {Deciphering the biotransformation
mechanism of dialkylresorcinols by
CYP4F11},
journal = {Bioorganic Chemistry},
volume = {131},
pages = {106330},
abstract = {Cytochrome P450 enzymes (CYPs) are one of
the most important classes of oxidative
enzymes in the human body, carrying out
metabolism of various exogenous and
endogenous substrates. In order to expand
the knowledge of these enzymes’
specificity and to obtain new natural
product derivatives, CYP4F11, a cytochrome
P450 monooxygenase, was used in the
biotransformation of dialkylresorcinols 1
and 2, a pair of antibiotic microbial
natural products. This investigation
resulted in four biotransformation
products including two oxidative products:
a hydroxylated derivative (3) and a
carboxylic acid derivative (4). In
addition, acetylated (5) and esterified
products (6) were isolated, formed by
further metabolism by endogenous yeast
enzymes. Oxidative transformations were
highly regioselective, and took place
exclusively at the ω-position of the C-5
alkyl chain. Homology modeling studies
revealed that optimal hydrogen bonding
between 2 and the enzyme can only be
established with the C-5 alkyl chain
pointing towards the heme. The
closely-related CYP4F12 was not capable of
oxidizing the dialkylresorcinol 2.
Modeling experiments rationalize these
differences by the different shapes of the
binding pockets with respect to the
non-oxidized alkyl chain. Antimicrobial
testing indicated that the presence of
polar groups on the side-chains reduces
the antibiotic activity of the
dialkylresorcinols.},
keywords = {Cytochrome P450 Homology modeling
Biotransformation Natural products
Dialkylresorcinols Fission yeast
Recombinant expression},
ISSN = {0045-2068},
DOI = {10.1016/j.bioorg.2022.106330},
url = {https://www.sciencedirect.com/science/article/pii/S0045206822007374},
year = {2023},
type = {Journal Article}
}
x
Deciphering the biotransformation mechanism of dialkylresorcinols by CYP4F11
Cytochrome P450 enzymes (CYPs) are one of the most important classes of oxidative enzymes in the human body, carrying out metabolism of various exogenous and endogenous substrates. In order to expand the knowledge of these enzymes’ specificity and to obtain new natural product derivatives, CYP4F11, a cytochrome P450 monooxygenase, was used in the biotransformation of dialkylresorcinols 1 and 2, a pair of antibiotic microbial natural products. This investigation resulted in four biotransformation products including two oxidative products: a hydroxylated derivative (3) and a carboxylic acid derivative (4). In addition, acetylated (5) and esterified products (6) were isolated, formed by further metabolism by endogenous yeast enzymes. Oxidative transformations were highly regioselective, and took place exclusively at the ω-position of the C-5 alkyl chain. Homology modeling studies revealed that optimal hydrogen bonding between 2 and the enzyme can only be established with the C-5 alkyl chain pointing towards the heme. The closely-related CYP4F12 was not capable of oxidizing the dialkylresorcinol 2. Modeling experiments rationalize these differences by the different shapes of the binding pockets with respect to the non-oxidized alkyl chain. Antimicrobial testing indicated that the presence of polar groups on the side-chains reduces the antibiotic activity of the dialkylresorcinols.
R. Wamser, S. Pach, C. Arkona, M. Baumgardt, U. B. A. Aziz, A. C. Hocke, G. Wolber, and J. Rademann. A Critical Study on Acylating and Covalent Reversible Fragment Inhibitors of SARS-CoV-2 Main Protease Targeting the S1 Site with Pyridine, ChemMedChem, 18:e202200635, 2023.
Links:
[doi:10.1002/cmdc.202200635]
[show BibTeX]
[show abstract]
x
@article{RN333,
author = {Wamser, Rebekka and Pach, Szymon and
Arkona, Christoph and Baumgardt, Morris
and Aziz, Umer Bin Abdul and Hocke,
Andreas C. and Wolber, Gerhard and
Rademann, Jörg},
title = {A Critical Study on Acylating and
Covalent Reversible Fragment Inhibitors of
SARS-CoV-2 Main Protease Targeting the S1
Site with Pyridine},
journal = {ChemMedChem},
volume = {18},
pages = {e202200635},
note = {https://doi.org/10.1002/cmdc.202200635},
abstract = {Abstract SARS coronavirus main proteases
(3CL proteases) have been validated as
pharmacological targets for the treatment
of coronavirus infections. Current
inhibitors of SARS main protease,
including the clinically admitted drug
nirmatrelvir are peptidomimetics with the
downsides of this class of drugs including
limited oral bioavailability, cellular
permeability, and rapid metabolic
degradation. Here, we investigate covalent
fragment inhibitors of SARS Mpro as
potential alternatives to peptidomimetic
inhibitors in use today. Starting from
inhibitors acylating the enzyme's active
site, a set of reactive fragments was
synthesized, and the inhibitory potency
was correlated with the chemical stability
of the inhibitors and the kinetic
stability of the covalent enzyme-inhibitor
complex. We found that all tested
acylating carboxylates, several of them
published prominently, were hydrolyzed in
assay buffer and the inhibitory
acyl-enzyme complexes were rapidly
degraded leading to the irreversible
inactivation of these drugs. Acylating
carbonates were found to be more stable
than acylating carboxylates, however, were
inactive in infected cells. Finally,
reversibly covalent fragments were
investigated as chemically stable SARS
CoV-2 inhibitors. Best was a
pyridine-aldehyde fragment with an IC50 of
1.8??M at a molecular weight of 211?g/mol,
showing that pyridine fragments indeed are
able to block the active site of
SARS-CoV-2 main protease.},
ISSN = {1860-7179},
DOI = {10.1002/cmdc.202200635},
url = {https://doi.org/10.1002/cmdc.202200635
https://chemistry-europe.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cmdc.202200635?download= true},
year = {2023},
type = {Journal Article}
}
x
A Critical Study on Acylating and Covalent Reversible Fragment Inhibitors of SARS-CoV-2 Main Protease Targeting the S1 Site with Pyridine
Abstract SARS coronavirus main proteases (3CL proteases) have been validated as pharmacological targets for the treatment of coronavirus infections. Current inhibitors of SARS main protease, including the clinically admitted drug nirmatrelvir are peptidomimetics with the downsides of this class of drugs including limited oral bioavailability, cellular permeability, and rapid metabolic degradation. Here, we investigate covalent fragment inhibitors of SARS Mpro as potential alternatives to peptidomimetic inhibitors in use today. Starting from inhibitors acylating the enzyme's active site, a set of reactive fragments was synthesized, and the inhibitory potency was correlated with the chemical stability of the inhibitors and the kinetic stability of the covalent enzyme-inhibitor complex. We found that all tested acylating carboxylates, several of them published prominently, were hydrolyzed in assay buffer and the inhibitory acyl-enzyme complexes were rapidly degraded leading to the irreversible inactivation of these drugs. Acylating carbonates were found to be more stable than acylating carboxylates, however, were inactive in infected cells. Finally, reversibly covalent fragments were investigated as chemically stable SARS CoV-2 inhibitors. Best was a pyridine-aldehyde fragment with an IC50 of 1.8??M at a molecular weight of 211?g/mol, showing that pyridine fragments indeed are able to block the active site of SARS-CoV-2 main protease.
F. Wunsch, T. N. Nguyen, G. Wolber, and M. Bermudez. Structural determinants of sphingosine-1-phosphate receptor selectivity, Arch Pharm (Weinheim), :e2300387, 2023.
Links:
[doi:10.1002/ardp.202300387]
[show BibTeX]
[show abstract]
x
@article{RN340,
author = {Wunsch, F. and Nguyen, T. N. and Wolber,
G. and Bermudez, M.},
title = {Structural determinants of
sphingosine-1-phosphate receptor
selectivity},
journal = {Arch Pharm (Weinheim)},
pages = {e2300387},
note = {Wunsch, Friederike Nguyen, Trung Ngoc
Wolber, Gerhard Bermudez, Marcel eng
Joachim Herz Stiftung/ 407626949/German
Research Foundation (Deutsche
Forschungsgemeinschaft)/ Germany
2023/10/09 Arch Pharm (Weinheim). 2023 Oct
8:e2300387. doi: 10.1002/ardp.202300387.},
abstract = {Fingolimod, the prodrug of
fingolimod-1-phosphate (F1P), was the
first sphingosine-1-phosphate receptor
(S1PR) modulator approved for multiple
sclerosis. F1P unselectively targets all
five S1PR subtypes. While agonism
(functional antagonism via receptor
internalization) at S1PR(1) leads to the
desired immune modulatory effects, agonism
at S1PR(3) is associated with cardiac
adverse effects. This motivated the
development of S1PR(3) -sparing compounds
and led to a second generation of
S1PR(1,5) -selective ligands like
siponimod and ozanimod. Our method
combines molecular dynamics simulations
and three-dimensional pharmacophores
(dynophores) and enables the elucidation
of S1PR subtype-specific binding site
characteristics, visualizing also subtle
differences in receptor-ligand
interactions. F1P and the endogenous
ligand sphingosine-1-phosphate bind to the
orthosteric pocket of all S1PRs, but show
different binding mode dynamics,
uncovering potential starting points for
the development of subtype-specific
ligands. Our study contributes to the
mechanistic understanding of the
selectivity profile of approved drugs like
ozanimod and siponimod and pharmaceutical
tool compounds like CYM5541.},
keywords = {Gpcr drug design molecular dynamics
pharmacophores selectivity},
ISSN = {1521-4184 (Electronic) 0365-6233
(Linking)},
DOI = {10.1002/ardp.202300387},
url = {https://www.ncbi.nlm.nih.gov/pubmed/37806764
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ardp.202300387?download= true},
year = {2023},
type = {Journal Article}
}
x
Structural determinants of sphingosine-1-phosphate receptor selectivity
Fingolimod, the prodrug of fingolimod-1-phosphate (F1P), was the first sphingosine-1-phosphate receptor (S1PR) modulator approved for multiple sclerosis. F1P unselectively targets all five S1PR subtypes. While agonism (functional antagonism via receptor internalization) at S1PR(1) leads to the desired immune modulatory effects, agonism at S1PR(3) is associated with cardiac adverse effects. This motivated the development of S1PR(3) -sparing compounds and led to a second generation of S1PR(1,5) -selective ligands like siponimod and ozanimod. Our method combines molecular dynamics simulations and three-dimensional pharmacophores (dynophores) and enables the elucidation of S1PR subtype-specific binding site characteristics, visualizing also subtle differences in receptor-ligand interactions. F1P and the endogenous ligand sphingosine-1-phosphate bind to the orthosteric pocket of all S1PRs, but show different binding mode dynamics, uncovering potential starting points for the development of subtype-specific ligands. Our study contributes to the mechanistic understanding of the selectivity profile of approved drugs like ozanimod and siponimod and pharmaceutical tool compounds like CYM5541.
J. Zhao, X. Zhang, Y. Wang, H. Huang, S. Sharma, S. S. Sharma, C. A. Wolf, S. Liu, G. Wolber, E. J. Sorensen, and M. Bureik. Exploring the chemical space of Proluciferins as probe substrates for human Cytochrome P450 enzymes, Appl Biochem Biotech, 195:1042-1058, 2023.
Links:
[doi:10.1007/s12010-022-04184-0]
[show BibTeX]
[show abstract]
x
@article{RN328,
author = {Zhao, Jie and Zhang, Xue and Wang, Yueyin
and Huang, Huimin and Sharma, Shishir and
Sharma, Sangeeta Shrestha and Wolf,
Clemens Alexander and Liu, Sijie and
Wolber, Gerhard and Sorensen, Erik J. and
Bureik, Matthias},
title = {Exploring the chemical space of
Proluciferins as probe substrates for
human Cytochrome P450 enzymes},
journal = {Applied Biochemistry and Biotechnology},
volume = {195},
pages = {1042-1058},
abstract = {We report the synthesis of 21 new
proluciferin compounds that bear a small
aliphatic ether group connected to the
6’ hydroxy function of firefly luciferin
and either contain an acid or methyl ester
function at the dihydrothiazole ring. Each
of these compounds was found to be a
substrate for some members of the human
CYP1 and CYP3 families; a total of 92 new
enzyme–substrate pairs were identified.
In a screen of the whole human P450
complement (CYPome) with three selected
proluciferin acid substrates, another 13
enzyme–substrate pairs were detected,
which involve enzymes belonging to the
CYP2, CYP4, CYP7, CYP21, and CYP27
families. All in all, we identified new
probe substrates for members of seven out
of 18 human CYP families.},
ISSN = {1559-0291},
DOI = {10.1007/s12010-022-04184-0},
url = {https://doi.org/10.1007/s12010-022-04184-0
https://link.springer.com/content/pdf/10.1007/s12010-022-04184-0.pdf},
year = {2023},
type = {Journal Article}
}
x
Exploring the chemical space of Proluciferins as probe substrates for human Cytochrome P450 enzymes
We report the synthesis of 21 new proluciferin compounds that bear a small aliphatic ether group connected to the 6’ hydroxy function of firefly luciferin and either contain an acid or methyl ester function at the dihydrothiazole ring. Each of these compounds was found to be a substrate for some members of the human CYP1 and CYP3 families; a total of 92 new enzyme–substrate pairs were identified. In a screen of the whole human P450 complement (CYPome) with three selected proluciferin acid substrates, another 13 enzyme–substrate pairs were detected, which involve enzymes belonging to the CYP2, CYP4, CYP7, CYP21, and CYP27 families. All in all, we identified new probe substrates for members of seven out of 18 human CYP families.
2022
[186]
D. Akman, K. Denzinger, S. Huang, J. T. Lee, J. W. Nafie, G. Wolber, G. W. Zamponi, D. W. Armstrong, and M. G. Gunduz. Focusing on C-4 position of Hantzsch 1,4-dihydropyridines: Molecular modifications, enantioseparation, and binding mechanism to L- and T-type calcium channels, Eur J Med Chem, 244:114787, 2022.
Links:
[doi:10.1016/j.ejmech.2022.114787]
[show BibTeX]
[show abstract]
x
@article{RN323,
author = {Akman, Dilara and Denzinger, Katrin and
Huang, Sun and Lee, J. T. and Nafie,
Jordan W. and Wolber, Gerhard and Zamponi,
Gerald W. and Armstrong, Daniel W. and
Gunduz, Miyase Gozde},
title = {Focusing on C-4 position of Hantzsch
1,4-dihydropyridines: Molecular
modifications, enantioseparation, and
binding mechanism to L- and T-type calcium
channels},
journal = {European Journal of Medicinal Chemistry},
volume = {244},
pages = {114787},
abstract = {1,4-Dihydropyridines (DHPs) represent the
blockbuster class of L-type calcium
channel blockers that have tremendous
therapeutic value against cardiovascular
conditions. Due to their abilities to
additionally target other subtypes of
calcium channels, DHPs are also considered
promising molecules for the treatment of
neurological and psychiatric disorders.
Having been in the market for more than
forty years, DHP is one of the most
modified scaffolds for the development of
novel molecules acting on calcium
channels. Taking the chemical structures
of approved DHPs into account, it is
noteworthy that C-4 position is the least
modified part of the ring system.
Therefore, in the present study, we
focused on this location and carried out
various molecular modifications to obtain
twelve potential calcium channel blockers
with a DHP-based hexahydroquinoline
scaffold (DA1-DA12). The whole-cell patch
clamp technique applied to analyze the
blocking ability of the synthesized
compounds on both L- (Cav1.2) and T-
(Cav3.2) type calcium channels revealed
five blockers with different selectivity
profiles. Introducing naphthyl moiety onto
the C-4 position of the main scaffold led
to the identification of a selective
blocker of Cav1.2 (DA8). The
benzodioxole-substituted derivative (DA1)
was the most potent and selective Cav3.2
inhibitor, therefore, its enantiomers were
separated using HPLC on a chiral
stationary phase. Retesting single isomers
on Cav3.2 revealed that S-enantiomer was
mainly responsible for the block. Finally,
DA compounds were docked into two
generated homology models of L- and T-type
calcium channels. Molecular dynamics (MD)
simulations and 3D pharmacophore modeling
provided further insights into the
detailed binding mechanism of DHPs to
Cav1.2 as well as to Cav3.2.},
keywords = {Hantzsch synthesis Hexahydroquinoline
Chiral center Patch clamp Molecular
dynamics 3D pharmacophore},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2022.114787},
url = {https://www.sciencedirect.com/science/article/pii/S0223523422006894},
year = {2022},
type = {Journal Article}
}
x
Focusing on C-4 position of Hantzsch 1,4-dihydropyridines: Molecular modifications, enantioseparation, and binding mechanism to L- and T-type calcium channels
1,4-Dihydropyridines (DHPs) represent the blockbuster class of L-type calcium channel blockers that have tremendous therapeutic value against cardiovascular conditions. Due to their abilities to additionally target other subtypes of calcium channels, DHPs are also considered promising molecules for the treatment of neurological and psychiatric disorders. Having been in the market for more than forty years, DHP is one of the most modified scaffolds for the development of novel molecules acting on calcium channels. Taking the chemical structures of approved DHPs into account, it is noteworthy that C-4 position is the least modified part of the ring system. Therefore, in the present study, we focused on this location and carried out various molecular modifications to obtain twelve potential calcium channel blockers with a DHP-based hexahydroquinoline scaffold (DA1-DA12). The whole-cell patch clamp technique applied to analyze the blocking ability of the synthesized compounds on both L- (Cav1.2) and T- (Cav3.2) type calcium channels revealed five blockers with different selectivity profiles. Introducing naphthyl moiety onto the C-4 position of the main scaffold led to the identification of a selective blocker of Cav1.2 (DA8). The benzodioxole-substituted derivative (DA1) was the most potent and selective Cav3.2 inhibitor, therefore, its enantiomers were separated using HPLC on a chiral stationary phase. Retesting single isomers on Cav3.2 revealed that S-enantiomer was mainly responsible for the block. Finally, DA compounds were docked into two generated homology models of L- and T-type calcium channels. Molecular dynamics (MD) simulations and 3D pharmacophore modeling provided further insights into the detailed binding mechanism of DHPs to Cav1.2 as well as to Cav3.2.
S. El Deeb, A. E. Ibrahim, A. Al-Harrasi, G. Wolber, and R. Gust. Validated capillary zone electrophoresis method for impurity profiling and determination of niII(3-ome-salophene), Separations, 9(2):25, 2022.
Links:
[doi:10.3390/separations9020025]
[show BibTeX]
[show abstract]
x
@article{RN317,
author = {El Deeb, Sami and Ibrahim, Adel Ehab and
Al-Harrasi, Ahmed and Wolber, Gerhard and
Gust, Ronald},
title = {Validated capillary zone electrophoresis
method for impurity profiling and
determination of niII(3-ome-salophene)},
journal = {Separations},
volume = {9},
number = {2},
pages = {25},
abstract = {A capillary zone electrophoresis method
was developed for the determination of
NiII(3-OMe-salophene), a substance with
anticancer activity in vitro. A fused
silica capillary (56 cm × 100 µm) was
used for this purpose. The method was
optimized in terms of parameters affecting
the electrophoretic conditions in order to
optimize separation efficiency and total
time of migration. The analysis was best
performed using an operating buffer of 50
mM borate, adjusted to pH 9.3, mixed with
acetonitrile (50%, v/v) as organic
modifier. Injections were performed
hydrodynamically by applying a pressure of
50 mbar for 8 s, and a 30 kV separation
voltage was selected at 25 ◦C. Detection
was carried out at 250 nm using diode
array detector (DAD). The method allowed
the separation of NiII(3-OMe-salophene)
from four other structurally related
impurities in a total migration time (tm)
of 8 min. Peak identification was achieved
using the standard reference of individual
impurities. The purity of the migrated
NiII(3-OMe-salophene) was confirmed by
Ultra-violet (UV) scan overlay depending
on DAD. The linear ranges for the
determination of NiII(3-OMe-salophene) was
400–20,000 ng mL−1 with limit of
detection (LOD) of 120 ng mL−1.
Acceptable intra-day and inter-day
precisions were achieved (%relative
standard deviation (RSD) results were less
than 0.76% and 0.30%, respectively). The
proposed method was assessed for greenness
and compared to reported methodologies to
prove superiority.},
ISSN = {2297-8739},
DOI = {10.3390/separations9020025},
year = {2022},
type = {Journal Article}
}
x
Validated capillary zone electrophoresis method for impurity profiling and determination of niII(3-ome-salophene)
A capillary zone electrophoresis method was developed for the determination of NiII(3-OMe-salophene), a substance with anticancer activity in vitro. A fused silica capillary (56 cm × 100 µm) was used for this purpose. The method was optimized in terms of parameters affecting the electrophoretic conditions in order to optimize separation efficiency and total time of migration. The analysis was best performed using an operating buffer of 50 mM borate, adjusted to pH 9.3, mixed with acetonitrile (50%, v/v) as organic modifier. Injections were performed hydrodynamically by applying a pressure of 50 mbar for 8 s, and a 30 kV separation voltage was selected at 25 ◦C. Detection was carried out at 250 nm using diode array detector (DAD). The method allowed the separation of NiII(3-OMe-salophene) from four other structurally related impurities in a total migration time (tm) of 8 min. Peak identification was achieved using the standard reference of individual impurities. The purity of the migrated NiII(3-OMe-salophene) was confirmed by Ultra-violet (UV) scan overlay depending on DAD. The linear ranges for the determination of NiII(3-OMe-salophene) was 400–20,000 ng mL−1 with limit of detection (LOD) of 120 ng mL−1. Acceptable intra-day and inter-day precisions were achieved (%relative standard deviation (RSD) results were less than 0.76% and 0.30%, respectively). The proposed method was assessed for greenness and compared to reported methodologies to prove superiority.
Y. Lu, X. Liu, R. Lotfy, S. Liu, A. F. Tesfa, G. Wolber, M. Bureik, and B. R. Clark. Experimental and computational studies on the biotransformation of pseudopyronines with human Cytochrome P450 CYP4F2, J Nat Prod, :, 2022.
Links:
[doi:10.1021/acs.jnatprod.2c00616]
[show BibTeX]
[show abstract]
x
@article{RN326,
author = {Lu, Ya and Liu, Xueling and Lotfy, Rowaa
and Liu, Sijie and Tesfa, Abel Fekadu and
Wolber, Gerhard and Bureik, Matthias and
Clark, Benjamin R.},
title = {Experimental and computational studies on
the biotransformation of pseudopyronines
with human Cytochrome P450 CYP4F2},
journal = {Journal of Natural Products},
note = {doi: 10.1021/acs.jnatprod.2c00616},
abstract = {The secondary metabolite pseudopyronine
B, isolated from Pseudomonas mosselii P33,
was biotransformed by human P450 enzymes,
heterologously expressed in the fission
yeast Schizosaccharomyces pombe.
Small-scale studies confirmed that both
CYP4F2 and CYP4F3A were capable of
oxidizing the substrate, with the former
achieving a higher yield. In larger-scale
studies using CYP4F2, three new oxidation
products were obtained, the structures of
which were elucidated by UV–vis, 1D and
2D NMR, and HR-MS spectroscopy. These
corresponded to hydroxylated,
carboxylated, and ester derivatives
(1–3) of pseudopyronine B, all of which
had been oxidized exclusively at the
ω-position of the C-6 alkyl chain. In
silico homology modeling experiments
highlighted key interactions between
oxygen atoms of the pyrone ring and two
serine residues and a histidine residue of
CYP4F2, which hold the substrate in a
suitable orientation for oxidation at the
terminus of the C-6 alkyl chain.
Additional modeling studies with all three
pseudopyronines revealed that the
seven-carbon alkyl chain of pseudopyronine
B was the perfect length for oxidation,
with the terminal carbon lying close to
the heme iron. The antibacterial activity
of the substrates and three oxidation
products was also assessed, revealing that
oxidation at the ω-position removes all
antimicrobial activity. This study both
increases the range of known substrates
for human CYF4F2 and CYP4F3A enzymes and
demonstrates their utility in producing
additional natural product derivatives.},
ISSN = {0163-3864},
DOI = {10.1021/acs.jnatprod.2c00616},
url = {https://doi.org/10.1021/acs.jnatprod.2c00616},
year = {2022},
type = {Journal Article}
}
x
Experimental and computational studies on the biotransformation of pseudopyronines with human Cytochrome P450 CYP4F2
The secondary metabolite pseudopyronine B, isolated from Pseudomonas mosselii P33, was biotransformed by human P450 enzymes, heterologously expressed in the fission yeast Schizosaccharomyces pombe. Small-scale studies confirmed that both CYP4F2 and CYP4F3A were capable of oxidizing the substrate, with the former achieving a higher yield. In larger-scale studies using CYP4F2, three new oxidation products were obtained, the structures of which were elucidated by UV–vis, 1D and 2D NMR, and HR-MS spectroscopy. These corresponded to hydroxylated, carboxylated, and ester derivatives (1–3) of pseudopyronine B, all of which had been oxidized exclusively at the ω-position of the C-6 alkyl chain. In silico homology modeling experiments highlighted key interactions between oxygen atoms of the pyrone ring and two serine residues and a histidine residue of CYP4F2, which hold the substrate in a suitable orientation for oxidation at the terminus of the C-6 alkyl chain. Additional modeling studies with all three pseudopyronines revealed that the seven-carbon alkyl chain of pseudopyronine B was the perfect length for oxidation, with the terminal carbon lying close to the heme iron. The antibacterial activity of the substrates and three oxidation products was also assessed, revealing that oxidation at the ω-position removes all antimicrobial activity. This study both increases the range of known substrates for human CYF4F2 and CYP4F3A enzymes and demonstrates their utility in producing additional natural product derivatives.
T. Noonan, K. Denzinger, V. Talagayev, Y. Chen, K. Puls, C. A. Wolf, S. Liu, T. N. Nguyen, and G. Wolber. Mind the gap - deciphering GPCR pharmacology using 3D pharmacophores and artificial intelligence, Pharmaceuticals, 15(11):1304, 2022.
Links:
[doi:10.3390/ph15111304]
[show BibTeX]
[show abstract]
x
@article{RN327,
author = {Noonan, Theresa and Denzinger, Katrin and
Talagayev, Valerij and Chen, Yu and Puls,
Kristina and Wolf, Clemens Alexander and
Liu, Sijie and Nguyen, Trung Ngoc and
Wolber, Gerhard},
title = {Mind the gap - deciphering GPCR
pharmacology using 3D pharmacophores and
artificial intelligence},
journal = {Pharmaceuticals},
volume = {15},
number = {11},
pages = {1304},
abstract = {G protein-coupled receptors (GPCRs) are
amongst the most pharmaceutically relevant
and well-studied protein targets, yet
unanswered questions in the field leave
significant gaps in our understanding of
their nuanced structure and function.
Three-dimensional pharmacophore models are
powerful computational tools in in silico
drug discovery, presenting myriad
opportunities for the integration of GPCR
structural biology and cheminformatics.
This review highlights success stories in
the application of 3D pharmacophore
modeling to de novo drug design, the
discovery of biased and allosteric
ligands, scaffold hopping, QSAR analysis,
hit-to-lead optimization, GPCR
de-orphanization, mechanistic
understanding of GPCR pharmacology and the
elucidation of ligand–receptor
interactions. Furthermore, advances in the
incorporation of dynamics and machine
learning are highlighted. The review will
analyze challenges in the field of GPCR
drug discovery, detailing how 3D
pharmacophore modeling can be used to
address them. Finally, we will present
opportunities afforded by 3D pharmacophore
modeling in the advancement of our
understanding and targeting of GPCRs},
ISSN = {1424-8247},
DOI = {10.3390/ph15111304},
url = {https://www.mdpi.com/1424-8247/15/11/1304},
year = {2022},
type = {Journal Article}
}
x
Mind the gap - deciphering GPCR pharmacology using 3D pharmacophores and artificial intelligence
G protein-coupled receptors (GPCRs) are amongst the most pharmaceutically relevant and well-studied protein targets, yet unanswered questions in the field leave significant gaps in our understanding of their nuanced structure and function. Three-dimensional pharmacophore models are powerful computational tools in in silico drug discovery, presenting myriad opportunities for the integration of GPCR structural biology and cheminformatics. This review highlights success stories in the application of 3D pharmacophore modeling to de novo drug design, the discovery of biased and allosteric ligands, scaffold hopping, QSAR analysis, hit-to-lead optimization, GPCR de-orphanization, mechanistic understanding of GPCR pharmacology and the elucidation of ligand–receptor interactions. Furthermore, advances in the incorporation of dynamics and machine learning are highlighted. The review will analyze challenges in the field of GPCR drug discovery, detailing how 3D pharmacophore modeling can be used to address them. Finally, we will present opportunities afforded by 3D pharmacophore modeling in the advancement of our understanding and targeting of GPCRs
K. Puls, A. Olivé-Marti, S. Pach, B. Pinter, F. Erli, G. Wolber, and M. Spetea. In vitro, in vivo and In silico characterization of a novel kappa-opioid receptor antagonist, Pharmaceuticals, 15(6):680, 2022.
Links:
[doi:10.3390/ph15060680]
[show BibTeX]
[show abstract]
x
@article{RN320,
author = {Puls, Kristina and Olivé-Marti,
Aina-Leonor and Pach, Szymon and Pinter,
Birgit and Erli, Filippo and Wolber,
Gerhard and Spetea, Mariana},
title = {In vitro, in vivo and In silico
characterization of a novel kappa-opioid
receptor antagonist},
journal = {Pharmaceuticals},
volume = {15},
number = {6},
pages = {680},
abstract = {Kappa-opioid receptor (KOR) antagonists
are promising innovative therapeutics for
the treatment of the central nervous
system (CNS) disorders. The new scaffold
opioid ligand, Compound A, was originally
found as a mu-opioid receptor (MOR)
antagonist but its binding/selectivity and
activation profile at the KOR and
delta-opioid receptor (DOR) remain
elusive. In this study, we present an in
vitro, in vivo and in silico
characterization of Compound A by
revealing this ligand as a KOR antagonist
in vitro and in vivo. In the radioligand
competitive binding assay, Compound A
bound at the human KOR, albeit with
moderate affinity, but with increased
affinity than to the human MOR and without
specific binding at the human DOR, thus
displaying a preferential KOR selectivity
profile. Following subcutaneous
administration in mice, Compound A
effectively reverse the antinociceptive
effects of the prototypical KOR agonist,
U50,488. In silico investigations were
carried out to assess the structural
determinants responsible for opioid
receptor subtype selectivity of Compound
A. Molecular docking, molecular dynamics
simulations and dynamic pharmacophore
(dynophore) generation revealed
differences in the stabilization of the
chlorophenyl moiety of Compound A within
the opioid receptor binding pockets,
rationalizing the experimentally
determined binding affinity values. This
new chemotype bears the potential for
favorable ADMET properties and holds
promise for chemical optimization toward
the development of potential therapeutics.
View Full-Text},
ISSN = {1424-8247},
DOI = {10.3390/ph15060680},
url = {https://www.mdpi.com/1424-8247/15/6/680},
year = {2022},
type = {Journal Article}
}
x
In vitro, in vivo and In silico characterization of a novel kappa-opioid receptor antagonist
Kappa-opioid receptor (KOR) antagonists are promising innovative therapeutics for the treatment of the central nervous system (CNS) disorders. The new scaffold opioid ligand, Compound A, was originally found as a mu-opioid receptor (MOR) antagonist but its binding/selectivity and activation profile at the KOR and delta-opioid receptor (DOR) remain elusive. In this study, we present an in vitro, in vivo and in silico characterization of Compound A by revealing this ligand as a KOR antagonist in vitro and in vivo. In the radioligand competitive binding assay, Compound A bound at the human KOR, albeit with moderate affinity, but with increased affinity than to the human MOR and without specific binding at the human DOR, thus displaying a preferential KOR selectivity profile. Following subcutaneous administration in mice, Compound A effectively reverse the antinociceptive effects of the prototypical KOR agonist, U50,488. In silico investigations were carried out to assess the structural determinants responsible for opioid receptor subtype selectivity of Compound A. Molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation revealed differences in the stabilization of the chlorophenyl moiety of Compound A within the opioid receptor binding pockets, rationalizing the experimentally determined binding affinity values. This new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics. View Full-Text
K. Puls, H. Schmidhammer, G. Wolber, and M. Spetea. Mechanistic characterization of the pharmacological profile of hs-731, a peripherally acting opioid analgesic, at the µ-, δ, κ-opioid and nociceptin receptors, Molecules, 27(3):919, 2022.
Links:
[doi:10.3390/molecules27030919]
[show BibTeX]
[show abstract]
x
@article{RN318,
author = {Puls, Kristina and Schmidhammer, Helmut
and Wolber, Gerhard and Spetea, Mariana},
title = {Mechanistic characterization of the
pharmacological profile of hs-731, a
peripherally acting opioid analgesic, at
the µ-, δ, κ-opioid and nociceptin
receptors},
journal = {Molecules},
volume = {27},
number = {3},
pages = {919},
abstract = {Accumulated preclinical and clinical data
show that peripheral restricted opioids
provide pain relief with reduced side
effects. The peripherally acting opioid
analgesic HS-731 is a potent dual
μ-/δ-opioid receptor (MOR/DOR)
full agonist, and a weak, partial agonist
at the κ-opioid receptor (KOR).
However, its binding mode at the opioid
receptors remains elusive. Here, we
present a comprehensive in silico
evaluation of HS-731 binding at all opioid
receptors. We provide insights into
dynamic interaction patterns explaining
the different binding and activity of
HS-731 on the opioid receptors. For this
purpose, we conducted docking, performed
molecular dynamics (MD) simulations and
generated dynamic pharmacophores
(dynophores). Our results highlight two
residues important for HS-731 recognition
at the classical opioid receptors (MOR,
DOR and KOR), particular the conserved
residue 5.39 (K) and the non-conserved
residue 6.58 (MOR: K, DOR: W and KOR: E).
Furthermore, we assume a salt bridge
between the transmembrane helices (TM) 5
and 6 via K2275.39 and E2976.58 to be
responsible for the partial agonism of
HS-731 at the KOR. Additionally, we
experimentally demonstrated the absence of
affinity of HS-731 to the
nociceptin/orphanin FQ peptide (NOP)
receptor. We consider the morphinan phenol
Y1303.33 responsible for this affinity
lack. Y1303.33 points deep into the NOP
receptor binding pocket preventing HS-731
binding to the orthosteric binding pocket.
These findings provide significant
structural insights into HS-731
interaction pattern with the opioid
receptors that are important for
understanding the pharmacology of this
peripheral opioid analgesic.},
keywords = {GPCR opioid receptor HS-731 peripheral
opioid agonist analgesia binding
selectivity molecular docking molecular
dynamics simulations},
ISSN = {1420-3049},
DOI = {10.3390/molecules27030919},
year = {2022},
type = {Journal Article}
}
x
Mechanistic characterization of the pharmacological profile of hs-731, a peripherally acting opioid analgesic, at the µ-, δ, κ-opioid and nociceptin receptors
Accumulated preclinical and clinical data show that peripheral restricted opioids provide pain relief with reduced side effects. The peripherally acting opioid analgesic HS-731 is a potent dual μ-/δ-opioid receptor (MOR/DOR) full agonist, and a weak, partial agonist at the κ-opioid receptor (KOR). However, its binding mode at the opioid receptors remains elusive. Here, we present a comprehensive in silico evaluation of HS-731 binding at all opioid receptors. We provide insights into dynamic interaction patterns explaining the different binding and activity of HS-731 on the opioid receptors. For this purpose, we conducted docking, performed molecular dynamics (MD) simulations and generated dynamic pharmacophores (dynophores). Our results highlight two residues important for HS-731 recognition at the classical opioid receptors (MOR, DOR and KOR), particular the conserved residue 5.39 (K) and the non-conserved residue 6.58 (MOR: K, DOR: W and KOR: E). Furthermore, we assume a salt bridge between the transmembrane helices (TM) 5 and 6 via K2275.39 and E2976.58 to be responsible for the partial agonism of HS-731 at the KOR. Additionally, we experimentally demonstrated the absence of affinity of HS-731 to the nociceptin/orphanin FQ peptide (NOP) receptor. We consider the morphinan phenol Y1303.33 responsible for this affinity lack. Y1303.33 points deep into the NOP receptor binding pocket preventing HS-731 binding to the orthosteric binding pocket. These findings provide significant structural insights into HS-731 interaction pattern with the opioid receptors that are important for understanding the pharmacology of this peripheral opioid analgesic.
D. Stepanov, D. Buchmann, N. Schultze, G. Wolber, K. Schaufler, S. Guenther, and V. Belik. A combined bayesian and similarity-based approach for predicting E. coli biofilm inhibition by phenolic natural compounds, J Nat Prod, :, 2022.
Links:
[doi:10.1021/acs.jnatprod.2c00005]
[show BibTeX]
[show abstract]
x
@article{RN322,
author = {Stepanov, Dmitri and Buchmann, David and
Schultze, Nadin and Wolber, Gerhard and
Schaufler, Katharina and Guenther,
Sebastian and Belik, Vitaly},
title = {A combined bayesian and similarity-based
approach for predicting E. coli biofilm
inhibition by phenolic natural compounds},
journal = {Journal of Natural Products},
note = {doi: 10.1021/acs.jnatprod.2c00005},
abstract = {Screening for biofilm inhibition by
purified natural compounds is difficult
due to compounds’ chemical diversity and
limited commercial availability, combined
with time- and cost-intensiveness of the
laboratory process. In silico prediction
of chemical and biological properties of
molecules is a widely used technique when
experimental data availability is of
concern. At the same time, the performance
of predictive models directly depends on
the amount and quality of experimental
data. Driven by the interest in developing
a model for prediction of the antibiofilm
effect of phenolic natural compounds such
as flavonoids, we performed experimental
assessment of antibiofilm activity of 320
compounds from this subset of chemicals.
The assay was performed once on two
Escherichia coli strains on agar in
24-well microtiter plates. The inhibition
was assessed visually by detecting
morphological changes in macrocolonies.
Using the data obtained, we subsequently
trained a Bayesian logistic regression
model for prediction of biofilm
inhibition, which was combined with a
similarity-based method in order to
increase the overall sensitivity (at the
cost of accuracy). The quality of the
predictions was subsequently validated by
experimental assessment in three
independent experiments with two resistant
E. coli strains of 23 compounds absent in
the initial data set. The validation
demonstrated that the model may
successfully predict the targeted effect
as compared to the baseline accuracy.
Using a randomly selected database of
commercially available natural phenolics,
we obtained approximately 6.0% of active
compounds, whereas using our
prediction-based substance selection, the
percentage of phenolics found to be active
increased to 34.8%.},
ISSN = {0163-3864},
DOI = {10.1021/acs.jnatprod.2c00005},
url = {https://doi.org/10.1021/acs.jnatprod.2c00005},
year = {2022},
type = {Journal Article}
}
x
A combined bayesian and similarity-based approach for predicting E. coli biofilm inhibition by phenolic natural compounds
Screening for biofilm inhibition by purified natural compounds is difficult due to compounds’ chemical diversity and limited commercial availability, combined with time- and cost-intensiveness of the laboratory process. In silico prediction of chemical and biological properties of molecules is a widely used technique when experimental data availability is of concern. At the same time, the performance of predictive models directly depends on the amount and quality of experimental data. Driven by the interest in developing a model for prediction of the antibiofilm effect of phenolic natural compounds such as flavonoids, we performed experimental assessment of antibiofilm activity of 320 compounds from this subset of chemicals. The assay was performed once on two Escherichia coli strains on agar in 24-well microtiter plates. The inhibition was assessed visually by detecting morphological changes in macrocolonies. Using the data obtained, we subsequently trained a Bayesian logistic regression model for prediction of biofilm inhibition, which was combined with a similarity-based method in order to increase the overall sensitivity (at the cost of accuracy). The quality of the predictions was subsequently validated by experimental assessment in three independent experiments with two resistant E. coli strains of 23 compounds absent in the initial data set. The validation demonstrated that the model may successfully predict the targeted effect as compared to the baseline accuracy. Using a randomly selected database of commercially available natural phenolics, we obtained approximately 6.0% of active compounds, whereas using our prediction-based substance selection, the percentage of phenolics found to be active increased to 34.8%.
D. Thieme, P. Anielski, S. Rzeppa, C. A. Wolf, G. Wolber, and A. M. Keiler. Detection of 18-methyl steroids: Case report on a forensic urine sample and corresponding dietary supplements, Drug Testing and Analysis, 14(11-12):1864-1870, 2022.
Links:
[doi:10.1002/dta.3389]
[show BibTeX]
[show abstract]
x
@article{RN325,
author = {Thieme, Detlef and Anielski, Patricia and
Rzeppa, Sebastian and Wolf, Clemens A. and
Wolber, Gerhard and Keiler, Annekathrin
M.},
title = {Detection of 18-methyl steroids: Case
report on a forensic urine sample and
corresponding dietary supplements},
journal = {Drug Testing and Analysis},
volume = {14},
number = {11-12},
pages = {1864-1870},
abstract = {Abstract The detection of a putative
18-methyl-19-nortestosterone metabolite in
a forensic bodybuilder's urine sample
collected as part of a criminal proceeding
has triggered a follow-up investigation.
Four different dietary supplements in the
possession of the suspect were examined
with regard to possible precursor
steroids. This led to the detection of the
declared ingredient methoxydienone, which
was confirmed by both, GC–MSMS and
LC-HRMSMS. As neither
18-methyl-testosterone, nor
18-methyl-19-nortestosterone were
detectable in the supplements, the
possibility that the metabolite originates
from methoxydienone was investigated. For
this purpose, the metabolic fate of
methoxydienone was studied in vitro using
human HepG2 cells and in vivo by a single
oral administration. While the
18-methyl-19-nortestosterone metabolite
was not generated by HepG2 cells incubated
with methoxydienone, it was observed in
the urine samples collected at 2, 6, 10
and 24 h after methoxydienone
administration. Moreover, the potential
binding of methoxydienone as ligand to the
human androgen receptor was modelled in
silico in comparison with
18-methylnandrolone, for which androgen
receptor activation had been shown in an
in vitro approach before. In conclusion,
we could ascribe the presence of the
18-methyl-19-nortestosterone metabolite in
a forensic urine sample to originate from
methoxydienone present in dietary
supplements. Methoxydienone was observed
to slowly degrade by demethylation of the
methoxy substituent in liquid solutions.
While no compound-specific intermediates
were identified that allowed
differentiation from other 18-methyl
steroids, the 18-methyl-19-nortestosterone
metabolite proved to be a suitable marker
for reliable detection in doping
analysis.},
ISSN = {1942-7603},
DOI = {10.1002/dta.3389},
url = {https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/dta.3389},
year = {2022},
type = {Journal Article}
}
x
Detection of 18-methyl steroids: Case report on a forensic urine sample and corresponding dietary supplements
Abstract The detection of a putative 18-methyl-19-nortestosterone metabolite in a forensic bodybuilder's urine sample collected as part of a criminal proceeding has triggered a follow-up investigation. Four different dietary supplements in the possession of the suspect were examined with regard to possible precursor steroids. This led to the detection of the declared ingredient methoxydienone, which was confirmed by both, GC–MSMS and LC-HRMSMS. As neither 18-methyl-testosterone, nor 18-methyl-19-nortestosterone were detectable in the supplements, the possibility that the metabolite originates from methoxydienone was investigated. For this purpose, the metabolic fate of methoxydienone was studied in vitro using human HepG2 cells and in vivo by a single oral administration. While the 18-methyl-19-nortestosterone metabolite was not generated by HepG2 cells incubated with methoxydienone, it was observed in the urine samples collected at 2, 6, 10 and 24 h after methoxydienone administration. Moreover, the potential binding of methoxydienone as ligand to the human androgen receptor was modelled in silico in comparison with 18-methylnandrolone, for which androgen receptor activation had been shown in an in vitro approach before. In conclusion, we could ascribe the presence of the 18-methyl-19-nortestosterone metabolite in a forensic urine sample to originate from methoxydienone present in dietary supplements. Methoxydienone was observed to slowly degrade by demethylation of the methoxy substituent in liquid solutions. While no compound-specific intermediates were identified that allowed differentiation from other 18-methyl steroids, the 18-methyl-19-nortestosterone metabolite proved to be a suitable marker for reliable detection in doping analysis.
F. Yang, S. Liu, G. Wolber, M. Bureik, and M. K. Parr. Complete reaction phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 enzymes of the human UGT1 and UGT2 families, Int J Mol Sci, 23(13):7476, 2022.
Links:
[doi:10.3390/ijms23137476]
[show BibTeX]
[show abstract]
x
@article{RN321,
author = {Yang, Fan and Liu, Sijie and Wolber,
Gerhard and Bureik, Matthias and Parr,
Maria Kristina},
title = {Complete reaction phenotyping of
Propranolol and 4-Hydroxypropranolol with
the 19 enzymes of the human UGT1 and UGT2
families},
journal = {International Journal of Molecular
Sciences},
volume = {23},
number = {13},
pages = {7476},
abstract = {Propranolol is a competitive
non-selective beta-receptor antagonist
that is available on the market as a
racemic mixture. In the present study,
glucuronidation of propranolol and its
equipotent phase I metabolite
4-hydroxypropranolol by all 19 members of
the human UGT1 and UGT2 families was
monitored. UGT1A7, UGT1A9, UGT1A10 and
UGT2A1 were found to glucuronidate
propranolol, with UGT1A7, UGT1A9 and
UGT2A1 mainly acting on (S)-propranolol,
while UGT1A10 displays the opposite
stereoselectivity. UGT1A7, UGT1A9 and
UGT2A1 were also found to glucuronidate
4-hydroxypropranolol. In contrast to
propranolol, 4-hydroxypropranolol was
found to be glucuronidated by UGT1A8 but
not by UGT1A10. Additional
biotransformations with
4-methoxypropanolol demonstrated different
regioselectivities of these UGTs with
respect to the aliphatic and aromatic
hydroxy groups of the substrate. Modeling
and molecular docking studies were
performed to explain the stereoselective
glucuronidation of the substrates under
study.},
ISSN = {1422-0067},
DOI = {10.3390/ijms23137476},
url = {https://www.mdpi.com/1422-0067/23/13/7476},
year = {2022},
type = {Journal Article}
}
x
Complete reaction phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 enzymes of the human UGT1 and UGT2 families
Propranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was monitored. UGT1A7, UGT1A9, UGT1A10 and UGT2A1 were found to glucuronidate propranolol, with UGT1A7, UGT1A9 and UGT2A1 mainly acting on (S)-propranolol, while UGT1A10 displays the opposite stereoselectivity. UGT1A7, UGT1A9 and UGT2A1 were also found to glucuronidate 4-hydroxypropranolol. In contrast to propranolol, 4-hydroxypropranolol was found to be glucuronidated by UGT1A8 but not by UGT1A10. Additional biotransformations with 4-methoxypropanolol demonstrated different regioselectivities of these UGTs with respect to the aliphatic and aromatic hydroxy groups of the substrate. Modeling and molecular docking studies were performed to explain the stereoselective glucuronidation of the substrates under study.
J. Zhao, S. Liu, C. A. Wolf, G. Wolber, M. K. Parr, and M. Bureik. Changes in Alprazolam metabolism by CYP3A43 mutants, Biomedicines, 10(12):3022, 2022.
Links:
[doi:10.3390/biomedicines10123022]
[show BibTeX]
x
@article{RN329,
author = {Zhao, Jie and Liu, Sijie and Wolf,
Clemens Alexander and Wolber, Gerhard and
Parr, Maria Kristina and Bureik,
Matthias},
title = {Changes in Alprazolam metabolism by
CYP3A43 mutants},
journal = {Biomedicines},
volume = {10},
number = {12},
pages = {3022},
ISSN = {2227-9059},
DOI = {10.3390/biomedicines10123022},
url = {https://www.mdpi.com/2227-9059/10/12/3022},
year = {2022},
type = {Journal Article}
}
J. Zhao, D. Machalz, S. Liu, C. A. Wolf, G. Wolber, M. K. Parr, and M. Bureik. Metabolism of the antipsychotic drug olanzapine by CYP3A43, Xenobiotica, :1-29, 2022.
Links:
[doi:10.1080/00498254.2022.2078751]
[show BibTeX]
[show abstract]
x
@article{RN319,
author = {Zhao, Jie and Machalz, David and Liu,
Sijie and Wolf, Clemens Alexander and
Wolber, Gerhard and Parr, Maria Kristina
and Bureik, Matthias},
title = {Metabolism of the antipsychotic drug
olanzapine by CYP3A43},
journal = {Xenobiotica},
pages = {1-29},
note = {doi: 10.1080/00498254.2022.2078751},
abstract = {Abstract1. Olanzapine is an atypical
antipsychotic primarily used to treat
schizophrenia and bipolar disorder. An
intronic single nucleotide polymorphism
(SNP) that highly significantly predicts
increased olanzapine clearance (rs472660)
was previously identified in the CYP3A43
gene, which encodes a cytochrome P450
enzyme. But until now there was no
experimental evidence for the metabolism
of olanzapine by the CYP3A43 enzyme.2. In
the present study we provide this
evidence, together with a thorough
analysis of olanzapine metabolism by all
human CYP3A enzymes. We also rationalize
our findings by molecular docking
experiments. Moreover, we describe the
activities of several CYP3A43 mutants and
present the first enzymatic activity data
for the CYP3A43.3 variant; with respect to
prostate cancer, this polymorphic variant
is associated with both increased risk and
increased mortality. The catalytic
properties of the wild type enzyme and the
tumor mutant were analyzed by molecular
dynamics simulations, which fit very well
with the observed experimental results.3.
Our finding suggests that the SNP rs472660
likely causes an increased CYP3A43
expression level and demonstrate that,
depending on the substrate under study,
the tumor mutant CYP3A43.3 can have
increased activity in comparison to the
wild type enzyme CYP3A43.1.},
ISSN = {0049-8254},
DOI = {10.1080/00498254.2022.2078751},
url = {https://doi.org/10.1080/00498254.2022.2078751
https://www.tandfonline.com/doi/full/10.1080/00498254.2022.2078751},
year = {2022},
type = {Journal Article}
}
x
Metabolism of the antipsychotic drug olanzapine by CYP3A43
Abstract1. Olanzapine is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. An intronic single nucleotide polymorphism (SNP) that highly significantly predicts increased olanzapine clearance (rs472660) was previously identified in the CYP3A43 gene, which encodes a cytochrome P450 enzyme. But until now there was no experimental evidence for the metabolism of olanzapine by the CYP3A43 enzyme.2. In the present study we provide this evidence, together with a thorough analysis of olanzapine metabolism by all human CYP3A enzymes. We also rationalize our findings by molecular docking experiments. Moreover, we describe the activities of several CYP3A43 mutants and present the first enzymatic activity data for the CYP3A43.3 variant; with respect to prostate cancer, this polymorphic variant is associated with both increased risk and increased mortality. The catalytic properties of the wild type enzyme and the tumor mutant were analyzed by molecular dynamics simulations, which fit very well with the observed experimental results.3. Our finding suggests that the SNP rs472660 likely causes an increased CYP3A43 expression level and demonstrate that, depending on the substrate under study, the tumor mutant CYP3A43.3 can have increased activity in comparison to the wild type enzyme CYP3A43.1.
2021
[175]
A. Dolšak, D. Šribar, A. Scheffler, M. Grabowski, U. Švajger, S. Gobec, J. Holze, G. Weindl, G. Wolber, and M. Sova. Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structure–activity relationships, Eur J Med Chem, 225:113809, 2021.
Links:
[doi:10.1016/j.ejmech.2021.113809]
[show BibTeX]
[show abstract]
x
@article{RN311,
author = {Dolšak, Ana and Šribar, Dora and
Scheffler, Alexander and Grabowski, Maria
and Švajger, Urban and Gobec, Stanislav
and Holze, Janine and Weindl, Günther and
Wolber, Gerhard and Sova, Matej},
title = {Further hit optimization of
6-(trifluoromethyl)pyrimidin-2-amine based
TLR8 modulators: Synthesis, biological
evaluation and structure–activity
relationships},
journal = {European Journal of Medicinal Chemistry},
volume = {225},
pages = {113809},
abstract = {Toll-like receptor 8 (TLR8) is an
endosomal TLR that has an important role
in the innate human immune system, which
is involved in numerous pathological
conditions. Excessive activation of TLR8
can lead to inflammatory and autoimmune
diseases, which highlights the need for
development of TLR8 modulators. However,
only a few small-molecule modulators that
selectively target TLR8 have been
developed. Here, we report the synthesis
and systematic investigation of the
structure–activity relationships of a
series of novel TLR8 negative modulators
based on previously reported
6-(trifluoromethyl)pyrimidin-2-amine
derivatives. Four compounds showed
low-micromolar concentration-dependent
inhibition of TLR8-mediated signaling in
HEK293 cells. These data confirm that the
6-trifluoromethyl group and two other
substituents on positions 2 and 4 are
important structural elements of
pyrimidine-based TLR8 modulators.
Substitution of the main scaffold at
position 2 with a methylsulfonyl group or
para hydroxy/hydroxymethyl substituted
benzylamine is essential for potent
negative modulation of TLR8. Our
best-in-class TLR8-selective modulator 53
with IC50 value of 6.2 μM represents a
promising small-molecule chemical probe
for further optimization to a lead
compound with potent immunomodulatory
properties.},
keywords = {Toll-like receptors TLR8 Modulators
Pyrimidines Immunomodulation Autoimmune
disorders},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2021.113809},
url = {https://www.sciencedirect.com/science/article/pii/S0223523421006589},
year = {2021},
type = {Journal Article}
}
x
Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structure–activity relationships
Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structure–activity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-in-class TLR8-selective modulator 53 with IC50 value of 6.2 μM represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties.
M. Dumitrascuta, M. Bermudez, O. Trovato, J. De Neve, S. Ballet, G. Wolber, and M. Spetea. Antinociceptive efficacy of the μ-opioid/nociceptin peptide-based hybrid KGNOP1 in inflammatory pain without rewarding effects in mice: an experimental assessment and molecular docking, Molecules, 26(11):3267, 2021.
Links:
[doi:10.3390/molecules26113267]
[show BibTeX]
[show abstract]
x
@article{RN308,
author = {Dumitrascuta, Maria and Bermudez, Marcel
and Trovato, Olga and De Neve, Jolien and
Ballet, Steven and Wolber, Gerhard and
Spetea, Mariana},
title = {Antinociceptive efficacy of the
μ-opioid/nociceptin peptide-based hybrid
KGNOP1 in inflammatory pain without
rewarding effects in mice: an experimental
assessment and molecular docking},
journal = {Molecules},
volume = {26},
number = {11},
pages = {3267},
abstract = {Opioids are the most effective
analgesics, with most clinically available
opioids being agonists to the µ-opioid
receptor (MOR). The MOR is also
responsible for their unwanted effects,
including reward and opioid misuse leading
to the current public health crisis. The
imperative need for safer, non-addictive
pain therapies drives the search for novel
leads and new treatment strategies. In
this study, the recently discovered
MOR/nociceptin (NOP) receptor peptide
hybrid KGNOP1
(H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2)
was evaluated following subcutaneous
administration in mouse models of acute
(formalin test) and chronic inflammatory
pain (Complete Freund’s adjuvant-induced
paw hyperalgesia), liabilities of
spontaneous locomotion, conditioned place
preference, and the withdrawal syndrome.
KGNOP1 demonstrated dose-dependent
antinociceptive effects in the formalin
test, and efficacy in attenuating thermal
hyperalgesia with prolonged duration of
action. Antinociceptive effects of KGNOP1
were reversed by naltrexone and SB-612111,
indicating the involvement of both MOR and
NOP receptor agonism. In comparison with
morphine, KGNOP1 was more potent and
effective in mouse models of inflammatory
pain. Unlike morphine, KGNOP1 displayed
reduced detrimental liabilities, as no
locomotor impairment nor rewarding and
withdrawal effects were observed. Docking
of KGNOP1 to the MOR and NOP receptors and
subsequent 3D interaction pattern analyses
provided valuable insights into its
binding mode. The mixed MOR/NOP receptor
peptide KGNOP1 holds promise in the effort
to develop new analgesics for the
treatment of various pain states with
fewer MOR-mediated side effects,
particularly abuse and dependence
liabilities.},
ISSN = {1420-3049},
DOI = {10.3390/molecules26113267},
url = {https://www.mdpi.com/1420-3049/26/11/3267
https://res.mdpi.com/d_attachment/molecules/molecules-26-03267/article_deploy/molecules-26-03267-v3.pdf},
year = {2021},
type = {Journal Article}
}
x
Antinociceptive efficacy of the μ-opioid/nociceptin peptide-based hybrid KGNOP1 in inflammatory pain without rewarding effects in mice: an experimental assessment and molecular docking
Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund’s adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.
M. Janežič, K. Valjavec, K. B. Loboda, B. Herlah, I. Ogris, M. Kozorog, M. Podobnik, S. G. Grdadolnik, G. Wolber, and A. Perdih. Dynophore-based approach in virtual screening: a case of human DNA Topoisomerase IIα, Int J Mol Sci, 22(24):13474, 2021.
Links:
[doi:10.3390/ijms222413474]
[show BibTeX]
[show abstract]
x
@article{RN314,
author = {Janežič, Matej and Valjavec, Katja and
Loboda, Kaja Bergant and Herlah, Barbara
and Ogris, Iza and Kozorog, Mirijam and
Podobnik, Marjetka and Grdadolnik, Simona
Golič and Wolber, Gerhard and Perdih,
Andrej},
title = {Dynophore-based approach in virtual
screening: a case of human DNA
Topoisomerase IIα},
journal = {International Journal of Molecular
Sciences},
volume = {22},
number = {24},
pages = {13474},
abstract = {In this study, we utilized human DNA
topoisomerase IIα as a model target to
outline a dynophore-based approach to
catalytic inhibitor design. Based on MD
simulations of a known catalytic inhibitor
and the native ATP ligand analog, AMP-PNP,
we derived a joint dynophore model that
supplements the static
structure-based-pharmacophore information
with a dynamic component. Subsequently,
derived pharmacophore models were employed
in a virtual screening campaign of a
library of natural compounds. Experimental
evaluation identified flavonoid compounds
with promising topoisomerase IIα
catalytic inhibition and binding studies
confirmed interaction with the ATPase
domain. We constructed a binding model
through docking and extensively
investigated it with molecular dynamics MD
simulations, essential dynamics, and
MM-GBSA free energy calculations, thus
reconnecting the new results to the
initial dynophore-based screening model.
We not only demonstrate a new design
strategy that incorporates a dynamic
component of molecular recognition, but
also highlight new derivates in the
established flavonoid class of
topoisomerase II inhibitors.},
ISSN = {1422-0067},
DOI = {10.3390/ijms222413474},
url = {https://www.mdpi.com/1422-0067/22/24/13474},
year = {2021},
type = {Journal Article}
}
x
Dynophore-based approach in virtual screening: a case of human DNA Topoisomerase IIα
In this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the static structure-based-pharmacophore information with a dynamic component. Subsequently, derived pharmacophore models were employed in a virtual screening campaign of a library of natural compounds. Experimental evaluation identified flavonoid compounds with promising topoisomerase IIα catalytic inhibition and binding studies confirmed interaction with the ATPase domain. We constructed a binding model through docking and extensively investigated it with molecular dynamics MD simulations, essential dynamics, and MM-GBSA free energy calculations, thus reconnecting the new results to the initial dynophore-based screening model. We not only demonstrate a new design strategy that incorporates a dynamic component of molecular recognition, but also highlight new derivates in the established flavonoid class of topoisomerase II inhibitors.
J. Y. Liu, D. Machalz, G. Wolber, E. J. Sorensen, and M. Bureik. New proluciferin substrates for human CYP4 family enzymes, Appl Biochem Biotech, 193(1):218-237, 2021.
Links:
[doi:10.1007/s12010-020-03388-6]
[show BibTeX]
[show abstract]
x
@article{RN282,
author = {Liu, J. Y. and Machalz, D. and Wolber, G.
and Sorensen, E. J. and Bureik, M.},
title = {New proluciferin substrates for human
CYP4 family enzymes},
journal = {Applied Biochemistry and Biotechnology},
volume = {193},
number = {1},
pages = {218-237},
note = {Nh3ox Times Cited:0 Cited References
Count:48},
abstract = {We report the synthesis of seven new
proluciferins for convenient activity
determination of enzymes belonging to the
cytochrome P450 (CYP) 4 family.
Biotransformation of these probe
substrates was monitored using each of the
twelve human CYP4 family members, and
eight were found to act at least on one of
them. For all substrates, activity of
CYP4Z1 was always highest, while that of
CYP4F8 was always second highest. Site of
metabolism (SOM) predictions involving
SMARTCyp and docking experiments helped to
rationalize the observed activity trends
linked to substrate accessibility and
reactivity. We further report the first
homology model of CYP4F8 including
suggested substrate recognition residues
in a catalytically competent conformation
accessed by replica exchange solute
tempering (REST) simulations.},
keywords = {cytochrome p450 docking fission yeast
homo sapiens pharmacology proluciferin
site of metabolism prediction human
cytochrome-p450 enzyme
functional-characterization
activation-energies prediction cancer
autoantibodies identification selectivity
expression smartcyp},
ISSN = {0273-2289},
DOI = {10.1007/s12010-020-03388-6},
url = {Go to ISI://WOS:000564584100001
https://link.springer.com/content/pdf/10.1007/s12010-020-03388-6.pdf},
year = {2021},
type = {Journal Article}
}
x
New proluciferin substrates for human CYP4 family enzymes
We report the synthesis of seven new proluciferins for convenient activity determination of enzymes belonging to the cytochrome P450 (CYP) 4 family. Biotransformation of these probe substrates was monitored using each of the twelve human CYP4 family members, and eight were found to act at least on one of them. For all substrates, activity of CYP4Z1 was always highest, while that of CYP4F8 was always second highest. Site of metabolism (SOM) predictions involving SMARTCyp and docking experiments helped to rationalize the observed activity trends linked to substrate accessibility and reactivity. We further report the first homology model of CYP4F8 including suggested substrate recognition residues in a catalytically competent conformation accessed by replica exchange solute tempering (REST) simulations.
S. Loke, A. Stoll, D. Machalz, F. Botrè, G. Wolber, M. Bureik, and M. K. Parr. Corticosteroid biosynthesis revisited: No direct hydroxylation of Pregnenolone by Steroid 21-Hydroxylase, Front Endocrinol, 12(629):, 2021.
Links:
[doi:10.3389/fendo.2021.633785]
[show BibTeX]
[show abstract]
x
@article{RN307,
author = {Loke, Steffen and Stoll, Anna and
Machalz, David and Botrè, Francesco and
Wolber, Gerhard and Bureik, Matthias and
Parr, Maria Kristina},
title = {Corticosteroid biosynthesis revisited: No
direct hydroxylation of Pregnenolone by
Steroid 21-Hydroxylase},
journal = {Frontiers in Endocrinology},
volume = {12},
number = {629},
abstract = {Cytochrome P450s (CYPs) are an essential
family of enzymes in the human body. They
play a crucial role in metabolism,
especially in human steroid biosynthesis.
Reactions catalyzed by these enzymes are
highly stereo- and regio-specific. Lack or
severe malfunctions of CYPs can cause
severe diseases and even shorten life.
Hence, investigations on metabolic
reactions and structural requirements of
substrates are crucial to gain further
knowledge on the relevance of different
enzymes in the human body functions and
the origin of diseases. One key enzyme in
the biosynthesis of gluco- and
mineralocorticoids is CYP21A2, also known
as steroid 21-hydroxylase. To investigate
the steric and regional requirements of
substrates for this enzyme, we performed
whole-cell biotransformation assays using
a strain of fission yeast
Schizosaccharomyces pombe recombinantly
expressing CYP21A2. The progestogens
progesterone, pregnenolone, and their
17α-hydroxy-derivatives were used as
substrates. After incubation, samples were
analyzed using gas chromatography coupled
to mass spectrometry. For progesterone and
17α-hydroxyprogesterone, their
corresponding 21-hydroxylated metabolites
11-deoxycorticosterone and
11-deoxycortisol were detected, while
after incubation of pregnenolone and
17α-hydroxypregnenolone, no hydroxylated
product was observed. Findings were
confirmed with authentic reference
material. Molecular docking experiments
agree with these results and suggest that
interaction between the 3-oxo group and
arginine-234 of the enzyme is a strict
requirement. The presented results
demonstrate once more that the presence of
an oxo-group in position 3 of the steroid
is indispensable, while a 3-hydroxy group
prevents hydroxylation in position C-21 by
CYP21A2. This knowledge may be transferred
to other CYP21A2 substrates and hence help
to gain essential insights into steroid
metabolism.},
keywords = {corticosteroid,cytochrome
P450,CYP21,GC-MS,Fission yeast
(Schizosaccharomyces pombe),molecular
docking,steroid biosynthesis},
ISSN = {1664-2392},
DOI = {10.3389/fendo.2021.633785},
url = {https://www.frontiersin.org/article/10.3389/fendo.2021.633785},
year = {2021},
type = {Journal Article}
}
x
Corticosteroid biosynthesis revisited: No direct hydroxylation of Pregnenolone by Steroid 21-Hydroxylase
Cytochrome P450s (CYPs) are an essential family of enzymes in the human body. They play a crucial role in metabolism, especially in human steroid biosynthesis. Reactions catalyzed by these enzymes are highly stereo- and regio-specific. Lack or severe malfunctions of CYPs can cause severe diseases and even shorten life. Hence, investigations on metabolic reactions and structural requirements of substrates are crucial to gain further knowledge on the relevance of different enzymes in the human body functions and the origin of diseases. One key enzyme in the biosynthesis of gluco- and mineralocorticoids is CYP21A2, also known as steroid 21-hydroxylase. To investigate the steric and regional requirements of substrates for this enzyme, we performed whole-cell biotransformation assays using a strain of fission yeast Schizosaccharomyces pombe recombinantly expressing CYP21A2. The progestogens progesterone, pregnenolone, and their 17α-hydroxy-derivatives were used as substrates. After incubation, samples were analyzed using gas chromatography coupled to mass spectrometry. For progesterone and 17α-hydroxyprogesterone, their corresponding 21-hydroxylated metabolites 11-deoxycorticosterone and 11-deoxycortisol were detected, while after incubation of pregnenolone and 17α-hydroxypregnenolone, no hydroxylated product was observed. Findings were confirmed with authentic reference material. Molecular docking experiments agree with these results and suggest that interaction between the 3-oxo group and arginine-234 of the enzyme is a strict requirement. The presented results demonstrate once more that the presence of an oxo-group in position 3 of the steroid is indispensable, while a 3-hydroxy group prevents hydroxylation in position C-21 by CYP21A2. This knowledge may be transferred to other CYP21A2 substrates and hence help to gain essential insights into steroid metabolism.
D. Machalz, H. Li, W. Du, S. Sharma, S. Liu, M. Bureik, and G. Wolber. Discovery of a novel potent cytochrome P450 CYP4Z1 inhibitor, Eur J Med Chem, 215:113255, 2021.
Links:
[doi:10.1016/j.ejmech.2021.113255]
[show BibTeX]
[show abstract]
x
@article{RN303,
author = {Machalz, David and Li, Hongjie and Du,
Wei and Sharma, Shishir and Liu, Sijie and
Bureik, Matthias and Wolber, Gerhard},
title = {Discovery of a novel potent cytochrome
P450 CYP4Z1 inhibitor},
journal = {European Journal of Medicinal Chemistry},
volume = {215},
pages = {113255},
abstract = {Human cytochrome P450 enzyme CYP4Z1
represents a promising target for the
treatment of a multitude of malignancies
including breast cancer. The most active
known non-covalent inhibitor
(1-benzylimidazole) only shows low
micromolar affinity to CYP4Z1. We report a
new, highly active inhibitor for CYP4Z1
showing confirmed binding in an enzymatic
assay and an IC50 value of 63 ± 19 nM
in stably transfected MCF-7 cells
overexpressing CYP4Z1. The new inhibitor
was identified by a systematically
developed virtual screening protocol.
Binding was rationalized using a carefully
elaborated 3D pharmacophore hypothesis and
thoroughly characterized using extensive
molecular dynamics simulations and dynamic
3D pharmacophore (dynophore) analyses.
This novel inhibitor represents a valuable
pharmacological tool to accelerate
characterization of the still understudied
CYP4Z1 and might pave the way for a new
treatment strategy in CYP4Z1-associated
malignancies. The presented in silico
model for predicting CYP4Z1 interaction
provides novel mechanistic insights and
revealed that the drug ozagrel interacts
with CYP4Z1.},
keywords = {Breast cancer CYP4Z1 Enzyme inhibition
Molecular modeling Virtual screening 3D
pharmacophores},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2021.113255},
url = {https://www.sciencedirect.com/science/article/pii/S0223523421001045},
year = {2021},
type = {Journal Article}
}
x
Discovery of a novel potent cytochrome P450 CYP4Z1 inhibitor
Human cytochrome P450 enzyme CYP4Z1 represents a promising target for the treatment of a multitude of malignancies including breast cancer. The most active known non-covalent inhibitor (1-benzylimidazole) only shows low micromolar affinity to CYP4Z1. We report a new, highly active inhibitor for CYP4Z1 showing confirmed binding in an enzymatic assay and an IC50 value of 63 ± 19 nM in stably transfected MCF-7 cells overexpressing CYP4Z1. The new inhibitor was identified by a systematically developed virtual screening protocol. Binding was rationalized using a carefully elaborated 3D pharmacophore hypothesis and thoroughly characterized using extensive molecular dynamics simulations and dynamic 3D pharmacophore (dynophore) analyses. This novel inhibitor represents a valuable pharmacological tool to accelerate characterization of the still understudied CYP4Z1 and might pave the way for a new treatment strategy in CYP4Z1-associated malignancies. The presented in silico model for predicting CYP4Z1 interaction provides novel mechanistic insights and revealed that the drug ozagrel interacts with CYP4Z1.
D. Machalz, S. Pach, M. Bermudez, M. Bureik, and G. Wolber. Structural insights into understudied human cytochrome P450 enzymes, Drug Discov Today, 26(10):2456-2464, 2021.
Links:
[doi:10.1016/j.drudis.2021.06.006]
[show BibTeX]
[show abstract]
x
@article{RN306,
author = {Machalz, David and Pach, Szymon and
Bermudez, Marcel and Bureik, Matthias and
Wolber, Gerhard},
title = {Structural insights into understudied
human cytochrome P450 enzymes},
journal = {Drug Discovery Today},
volume = {26},
number = {10},
pages = {2456-2464},
abstract = {Human cytochrome P450 (CYP) enzymes are
widely known for their pivotal role in the
metabolism of drugs and other xenobiotics
as well as of endogenous chemicals. In
addition, CYPs are involved in numerous
pathophysiological pathways and, hence,
are therapeutically relevant. Remarkably,
a portion of promising CYP targets is
still understudied and, as a consequence,
untargeted, despite their huge therapeutic
potential. An increasing number of X-ray
and cryo-electron microscopy (EM)
structures for CYPs have recently provided
new insights into the structural basis of
CYP function and potential ligand binding.
This structural knowledge of CYP
functionality is essential for both
understanding metabolism and exploiting
understudied CYPs as drug targets. In this
review, we summarize and highlight
structural knowledge about this enzyme
class, with a focus on understudied CYPs
and resulting opportunities for
structure-based drug design. Teaser: This
review summarizes recent structural
insights into understudied cytochrome P450
enzymes. We highlight the impact of
molecular modeling for mechanistically
explaining pathophysiological effects
establishing understudied CYPs as
promising drug targets.},
keywords = {CYP Cytochrome P450 Protein structure
Cancer Genetic disease Mutation Homology
modeling Metabolism Molecular modeling},
ISSN = {1359-6446},
DOI = {10.1016/j.drudis.2021.06.006},
url = {https://www.sciencedirect.com/science/article/pii/S1359644621002786
https://www.sciencedirect.com/science/article/abs/pii/S1359644621002786?via%3Dihub},
year = {2021},
type = {Journal Article}
}
x
Structural insights into understudied human cytochrome P450 enzymes
Human cytochrome P450 (CYP) enzymes are widely known for their pivotal role in the metabolism of drugs and other xenobiotics as well as of endogenous chemicals. In addition, CYPs are involved in numerous pathophysiological pathways and, hence, are therapeutically relevant. Remarkably, a portion of promising CYP targets is still understudied and, as a consequence, untargeted, despite their huge therapeutic potential. An increasing number of X-ray and cryo-electron microscopy (EM) structures for CYPs have recently provided new insights into the structural basis of CYP function and potential ligand binding. This structural knowledge of CYP functionality is essential for both understanding metabolism and exploiting understudied CYPs as drug targets. In this review, we summarize and highlight structural knowledge about this enzyme class, with a focus on understudied CYPs and resulting opportunities for structure-based drug design. Teaser: This review summarizes recent structural insights into understudied cytochrome P450 enzymes. We highlight the impact of molecular modeling for mechanistically explaining pathophysiological effects establishing understudied CYPs as promising drug targets.
T. Meşeli, S. D. Doğan, M. G. Gündüz, Z. Kökbudak, S. Skaro Bogojevic, T. Noonan, S. Vojnovic, G. Wolber, and J. Nikodinovic-Runic. Design, synthesis, antibacterial activity evaluation and molecular modeling studies of new sulfonamides containing a sulfathiazole moiety, New J Chem, 45(18):8166-8177, 2021.
Links:
[doi:10.1039/D1NJ00150G]
[show BibTeX]
[show abstract]
x
@article{RN309,
author = {Meşeli, Tuğba and Doğan, Sengül Dilem
and Gündüz, Miyase Gözde and Kökbudak,
Zülbiye and Skaro Bogojevic, Sanja and
Noonan, Theresa and Vojnovic, Sandra and
Wolber, Gerhard and Nikodinovic-Runic,
Jasmina},
title = {Design, synthesis, antibacterial activity
evaluation and molecular modeling studies
of new sulfonamides containing a
sulfathiazole moiety},
journal = {New Journal of Chemistry},
volume = {45},
number = {18},
pages = {8166-8177},
abstract = {Sulfonamides represent the oldest
synthetic antibacterial agents; however,
their central position in controlling
bacterial diseases has been seriously
damaged by the development of widespread
resistance. Herein, we revisited
sulfathiazole, a commercial member of
antibacterial sulfa drugs, intending to
overcome sulfonamide resistance and
identify new drug candidates through
molecular modifications. We synthesized
twelve sulfonamides (SA1–SA12) by
replacing the amino group on the phenyl
ring with various substituents and
introducing a thiophene ring on the core
scaffold of sulfathiazole. The obtained
compounds and additionally two commercial
sulfonamides, sulfathiazole and
sulfadiazine, were extensively screened
for their antimicrobial activities. The
results indicated that new sulfonamides,
unlike traditional ones, were selectively
effective against various Staphylococcus
aureus strains. Introducing a bulky
lipophilic substituent at the para
position of the phenyl ring significantly
increased the antibacterial activities of
the compounds against Staphylococcus
aureus. The compounds demonstrating
favourable selectivity indices were
further evaluated for their membrane
potential perturbation and DNA interaction
properties. The obtained data showed that
these are not supporting mechanisms for
the antibacterial activities of the
modified sulfathiazole derivatives. In
order to rationalize the activity of the
three most active compounds, SA7, SA11 and
SA12, against S. aureus ATCC 25923, their
binding hypotheses within the catalytic
site of Staphylococcus aureus
dihydropteroate synthase, the validated
target enzyme of sulfonamides, were
generated via molecular docking and
further dissected using molecular dynamics
simulations and dynamic 3D pharmacophores
(dynophores).},
ISSN = {1144-0546},
DOI = {10.1039/D1NJ00150G},
url = {http://dx.doi.org/10.1039/D1NJ00150G
https://pubs.rsc.org/en/content/articlepdf/2021/nj/d1nj00150g},
year = {2021},
type = {Journal Article}
}
x
Design, synthesis, antibacterial activity evaluation and molecular modeling studies of new sulfonamides containing a sulfathiazole moiety
Sulfonamides represent the oldest synthetic antibacterial agents; however, their central position in controlling bacterial diseases has been seriously damaged by the development of widespread resistance. Herein, we revisited sulfathiazole, a commercial member of antibacterial sulfa drugs, intending to overcome sulfonamide resistance and identify new drug candidates through molecular modifications. We synthesized twelve sulfonamides (SA1–SA12) by replacing the amino group on the phenyl ring with various substituents and introducing a thiophene ring on the core scaffold of sulfathiazole. The obtained compounds and additionally two commercial sulfonamides, sulfathiazole and sulfadiazine, were extensively screened for their antimicrobial activities. The results indicated that new sulfonamides, unlike traditional ones, were selectively effective against various Staphylococcus aureus strains. Introducing a bulky lipophilic substituent at the para position of the phenyl ring significantly increased the antibacterial activities of the compounds against Staphylococcus aureus. The compounds demonstrating favourable selectivity indices were further evaluated for their membrane potential perturbation and DNA interaction properties. The obtained data showed that these are not supporting mechanisms for the antibacterial activities of the modified sulfathiazole derivatives. In order to rationalize the activity of the three most active compounds, SA7, SA11 and SA12, against S. aureus ATCC 25923, their binding hypotheses within the catalytic site of Staphylococcus aureus dihydropteroate synthase, the validated target enzyme of sulfonamides, were generated via molecular docking and further dissected using molecular dynamics simulations and dynamic 3D pharmacophores (dynophores).
R. Ottanà, P. Paoli, M. Cappiello, T. N. Nguyen, I. Adornato, A. Del Corso, M. Genovese, I. Nesi, R. Moschini, A. Naß, G. Wolber, and R. Maccari. In search for multi-target ligands as potential agents for diabetes mellitus and its complications—a structure-activity relationship study on inhibitors of aldose reductase and Protein Tyrosine Phosphatase 1B, Molecules, 26(2):330, 2021.
Links:
[doi:10.3390/molecules26020330]
[show BibTeX]
[show abstract]
x
@article{RN299,
author = {Ottanà, Rosaria and Paoli, Paolo and
Cappiello, Mario and Nguyen, Trung Ngoc
and Adornato, Ilenia and Del Corso,
Antonella and Genovese, Massimo and Nesi,
Ilaria and Moschini, Roberta and Naß,
Alexandra and Wolber, Gerhard and Maccari,
Rosanna},
title = {In search for multi-target ligands as
potential agents for diabetes mellitus and
its complications—a structure-activity
relationship study on inhibitors of aldose
reductase and Protein Tyrosine Phosphatase
1B},
journal = {Molecules},
volume = {26},
number = {2},
pages = {330},
abstract = {Diabetes mellitus (DM) is a complex
disease which currently affects more than
460 million people and is one of the
leading cause of death worldwide. Its
development implies numerous metabolic
dysfunctions and the onset of
hyperglycaemia-induced chronic
complications. Multiple ligands can be
rationally designed for the treatment of
multifactorial diseases, such as DM, with
the precise aim of simultaneously
controlling multiple pathogenic mechanisms
related to the disease and providing a
more effective and safer therapeutic
treatment compared to combinations of
selective drugs. Starting from our
previous findings that highlighted the
possibility to target both aldose
reductase (AR) and protein tyrosine
phosphatase 1B (PTP1B), two enzymes
strictly implicated in the development of
DM and its complications, we synthesised
3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic
acids and analogous 2-butenoic acid
derivatives, with the aim of balancing the
effectiveness of dual AR/PTP1B inhibitors
which we had identified as designed
multiple ligands (DMLs). Out of the tested
compounds, 4f exhibited well-balanced
AR/PTP1B inhibitory effects at low
micromolar concentrations, along with
interesting insulin-sensitizing activity
in murine C2C12 cell cultures. The SARs
here highlighted along with their
rationalization by in silico docking
experiments into both target enzymes
provide further insights into this class
of inhibitors for their development as
potential DML antidiabetic candidates.},
ISSN = {1420-3049},
DOI = {10.3390/molecules26020330},
url = {https://www.mdpi.com/1420-3049/26/2/330
https://res.mdpi.com/d_attachment/molecules/molecules-26-00330/article_deploy/molecules-26-00330-v3.pdf},
year = {2021},
type = {Journal Article}
}
x
In search for multi-target ligands as potential agents for diabetes mellitus and its complications—a structure-activity relationship study on inhibitors of aldose reductase and Protein Tyrosine Phosphatase 1B
Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.
S. Pach, T. N. Nguyen, J. Trimpert, D. Kunec, N. Osterrieder, and G. Wolber. ACE2 variants indicate potential SARS-CoV-2-Susceptibility in animals: An extensive molecular dynamics study, Mol Inf, 40(9):2100031, 2021.
Links:
[doi:10.1002/minf.202100031]
[show BibTeX]
x
@article{RN310,
author = {Pach, Szymon and Nguyen, Trung Ngoc and
Trimpert, Jakob and Kunec, Dusan and
Osterrieder, Nikolaus and Wolber,
Gerhard},
title = {ACE2 variants indicate potential
SARS-CoV-2-Susceptibility in animals: An
extensive molecular dynamics study},
journal = {Molecular Informatics},
volume = {40},
number = {9},
pages = {2100031},
DOI = {10.1002/minf.202100031},
url = {https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/minf.202100031?download=true},
year = {2021},
type = {Journal Article}
}
S. Sharma, S. Liu, P. Durairaj, D. Machalz, G. Wolber, and M. Bureik. A convenient test system for the identification of CYP4V2 inhibitors, Mol Vis, 27:601-607, 2021.
Links:
[show BibTeX]
[show abstract]
x
@article{RN312,
author = {Sharma, Shishir and Liu, Sijie and
Durairaj, Pradeepraj and Machalz, David
and Wolber, Gerhard and Bureik, Matthias},
title = {A convenient test system for the
identification of CYP4V2 inhibitors},
journal = {Molecular Vision},
volume = {27},
pages = {601-607},
note = {mv-v27-601.pdf},
abstract = {Purpose: Polymorphisms in the gene that
codes for the human cytochrome P450 enzyme
CYP4V2 are a cause of Bietti crystalline
dystrophy (BCD). Therefore, inhibition of
CYP4V2 activity may well be a cause of
visual disability. However, monitoring the
fatty acid hydroxylation reactions
catalyzed by this enzyme is tedious and
not well suited for inhibitor screening.
Methods: We investigated the use of
proluciferin compounds as probe substrates
for efficient and convenient determination
of CYP4V2 activity. Results: Ten
proluciferins were tested for conversion
by CYP4V2, and eight were found to be
substrates of this enzyme. One point
inhibitor assays were performed using
luciferin 6' 3-furfuryl ether methyl ester
(luciferin-3FEME) as the probe substrate
and 12 test compounds. As expected,
HET0016 had by far the strongest effect,
while two other compounds (including
osilodrostat) also displayed statistically
significant inhibitory potency. The half
maximal inhibitory concentration (IC50)
for HET0016 was determined to be 179 nM. A
recently identified potent inhibitor of
human CYP4Z1 was found not to inhibit
CYP4V2. To explore the selectivity of this
compound between CYP4Z1 and CYP4V2, we
developed a homology model of CYP4V2 and
conducted docking experiments.
Conclusions: We provide the first protocol
for a robust and convenient CYP4V2
inhibitor assay that does not depend on
fatty acid analysis but can be simply
monitored with luminescence. Moreover, we
demonstrate additional evidence for the
concern that compounds with CYP-inhibitory
properties may inhibit CYP4V2 activity and
thus, possibly cause visual disability.},
url = {http://www.molvis.org/molvis/v27/601},
year = {2021},
type = {Journal Article}
}
x
A convenient test system for the identification of CYP4V2 inhibitors
Purpose: Polymorphisms in the gene that codes for the human cytochrome P450 enzyme CYP4V2 are a cause of Bietti crystalline dystrophy (BCD). Therefore, inhibition of CYP4V2 activity may well be a cause of visual disability. However, monitoring the fatty acid hydroxylation reactions catalyzed by this enzyme is tedious and not well suited for inhibitor screening. Methods: We investigated the use of proluciferin compounds as probe substrates for efficient and convenient determination of CYP4V2 activity. Results: Ten proluciferins were tested for conversion by CYP4V2, and eight were found to be substrates of this enzyme. One point inhibitor assays were performed using luciferin 6' 3-furfuryl ether methyl ester (luciferin-3FEME) as the probe substrate and 12 test compounds. As expected, HET0016 had by far the strongest effect, while two other compounds (including osilodrostat) also displayed statistically significant inhibitory potency. The half maximal inhibitory concentration (IC50) for HET0016 was determined to be 179 nM. A recently identified potent inhibitor of human CYP4Z1 was found not to inhibit CYP4V2. To explore the selectivity of this compound between CYP4Z1 and CYP4V2, we developed a homology model of CYP4V2 and conducted docking experiments. Conclusions: We provide the first protocol for a robust and convenient CYP4V2 inhibitor assay that does not depend on fatty acid analysis but can be simply monitored with luminescence. Moreover, we demonstrate additional evidence for the concern that compounds with CYP-inhibitory properties may inhibit CYP4V2 activity and thus, possibly cause visual disability.
C. Tauber, R. Wamser, C. Arkona, M. Tuegend, U. B. Abdul Aziz, S. Pach, R. Schulz, D. Jochmans, G. Wolber, J. Neyts, and J. Rademann. Chemical evolution of antivirals against enterovirus D68 through protein-templated Knoevenagel reactions, Angewandte Chemie International Edition, 60(24):13294-13301, 2021.
Links:
[doi:10.1002/anie.202102074]
[show BibTeX]
[show abstract]
x
@article{RN305,
author = {Tauber, Carolin and Wamser, Rebekka and
Arkona, Christoph and Tuegend, Marisa and
Abdul Aziz, Umer Bin and Pach, Szymon and
Schulz, Robert and Jochmans, Dirk and
Wolber, Gerhard and Neyts, Johan and
Rademann, Joerg},
title = {Chemical evolution of antivirals against
enterovirus D68 through protein-templated
Knoevenagel reactions},
journal = {Angewandte Chemie International Edition},
volume = {60},
number = {24},
pages = {13294-13301},
note = {https://doi.org/10.1002/anie.202102074},
abstract = {The generation of bioactive molecules
from inactive precursors is a crucial step
in the chemical evolution of life,
however, mechanistic insights into this
aspect of abiogenesis are scarce. Here, we
investigate the protein-catalyzed
formation of antivirals by the 3C-protease
of enterovirus D68. The enzyme induces
aldol condensations yielding inhibitors
with antiviral activity in cells. Kinetic
and thermodynamic analyses reveal that the
bioactivity emerges from a dynamic
reaction system including inhibitor
formation, alkylation of the protein
target by the inhibitors, and competitive
addition of non-protein nucleophiles to
the inhibitors. The most active antivirals
are slowly reversible inhibitors with
elongated target residence times. The
study reveals first examples for the
chemical evolution of bio-actives through
protein-catalyzed, non-enzymatic
CC-couplings. The discovered mechanism
works under physiological conditions and
might constitute a native process of drug
development.},
keywords = {Chemical Evolution, Protein-templated
reactions, Antivirals, Protease
inhibitors, Fragment-based drug
discovery},
ISSN = {1433-7851},
DOI = {10.1002/anie.202102074},
url = {https://doi.org/10.1002/anie.202102074
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/anie.202102074?download= true},
year = {2021},
type = {Journal Article}
}
x
Chemical evolution of antivirals against enterovirus D68 through protein-templated Knoevenagel reactions
The generation of bioactive molecules from inactive precursors is a crucial step in the chemical evolution of life, however, mechanistic insights into this aspect of abiogenesis are scarce. Here, we investigate the protein-catalyzed formation of antivirals by the 3C-protease of enterovirus D68. The enzyme induces aldol condensations yielding inhibitors with antiviral activity in cells. Kinetic and thermodynamic analyses reveal that the bioactivity emerges from a dynamic reaction system including inhibitor formation, alkylation of the protein target by the inhibitors, and competitive addition of non-protein nucleophiles to the inhibitors. The most active antivirals are slowly reversible inhibitors with elongated target residence times. The study reveals first examples for the chemical evolution of bio-actives through protein-catalyzed, non-enzymatic CC-couplings. The discovered mechanism works under physiological conditions and might constitute a native process of drug development.
2020
[163]
M. Bermudez, M. Grabowski, M. S. Murgueitio, M. Tiemann, P. Varga, T. Rudolf, G. Wolber, G. Weindl, and J. Rademann. Biological characterization, mechanistic investigation and structure-activity relationships of chemically stable TLR2 antagonists, ChemMedChem, 15(14):1364-1371, 2020.
Links:
[doi:10.1002/cmdc.202000060]
[show BibTeX]
[show abstract]
x
@article{RN284,
author = {Bermudez, M. and Grabowski, M. and
Murgueitio, M. S. and Tiemann, M. and
Varga, P. and Rudolf, T. and Wolber, G.
and Weindl, G. and Rademann, J.},
title = {Biological characterization, mechanistic
investigation and structure-activity
relationships of chemically stable TLR2
antagonists},
journal = {Chemmedchem},
volume = {15},
number = {14},
pages = {1364-1371},
note = {Mm1dj Times Cited:0 Cited References
Count:34},
abstract = {Toll-like receptors (TLRs) build the
first barrier in the innate immune
response and therefore represent promising
targets for the modulation of inflammatory
processes. Recently, the
pyrogallol-containing TLR2 antagonists
CU-CPT22 and MMG-11 were reported;
however, their 1,2,3-triphenol motif
renders them highly susceptible to
oxidation and excludes them from use in
extended experiments under aerobic
conditions. Therefore, we have developed a
set of novel TLR2 antagonists (1-9) based
on the systematic variation of
substructures, linker elements, and the
hydrogen-bonding pattern of the pyrogallol
precursors by using chemically robust
building blocks. The novel series of
chemically stable and synthetically
accessible TLR2 antagonists (1-9) was
pharmacologically characterized, and the
potential binding modes of the active
compounds were evaluated structurally. Our
results provide new insights into
structure-activity relationships and allow
rationalization of structural binding
characteristics. Moreover, they support
the hypothesis that this class of TLR
ligands bind solely to TLR2 and do not
directly interact with TLR1 or TLR6 of the
functional heterodimer. The most active
compound from this series (6), is
chemically stable, nontoxic,
TLR2-selective, and shows a similar
activity with regard to the pyrogallol
starting points, thus indicating the
variability of the hydrogen bonding
pattern.},
keywords = {chemical synthesis inflammation molecular
modeling structure-based design tlr
selectivity toll-like receptors
pattern-recognition receptors discovery
peptides agonists design},
ISSN = {1860-7179},
DOI = {10.1002/cmdc.202000060},
url = {Go to ISI://WOS:000537253200001
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496872/pdf/CMDC-15-1364.pdf},
year = {2020},
type = {Journal Article}
}
x
Biological characterization, mechanistic investigation and structure-activity relationships of chemically stable TLR2 antagonists
Toll-like receptors (TLRs) build the first barrier in the innate immune response and therefore represent promising targets for the modulation of inflammatory processes. Recently, the pyrogallol-containing TLR2 antagonists CU-CPT22 and MMG-11 were reported; however, their 1,2,3-triphenol motif renders them highly susceptible to oxidation and excludes them from use in extended experiments under aerobic conditions. Therefore, we have developed a set of novel TLR2 antagonists (1-9) based on the systematic variation of substructures, linker elements, and the hydrogen-bonding pattern of the pyrogallol precursors by using chemically robust building blocks. The novel series of chemically stable and synthetically accessible TLR2 antagonists (1-9) was pharmacologically characterized, and the potential binding modes of the active compounds were evaluated structurally. Our results provide new insights into structure-activity relationships and allow rationalization of structural binding characteristics. Moreover, they support the hypothesis that this class of TLR ligands bind solely to TLR2 and do not directly interact with TLR1 or TLR6 of the functional heterodimer. The most active compound from this series (6), is chemically stable, nontoxic, TLR2-selective, and shows a similar activity with regard to the pyrogallol starting points, thus indicating the variability of the hydrogen bonding pattern.
K. Denzinger, T. N. Nguyen, T. Noonan, G. Wolber, and M. Bermudez. Biased ligands differentially shape the conformation of the extracellular loop region in 5-HT2B receptors, Int J Mol Sci, 21(24):9728, 2020.
Links:
[doi:10.3390/ijms21249728]
[show BibTeX]
[show abstract]
x
@article{RN301,
author = {Denzinger, Katrin and Nguyen, Trung Ngoc
and Noonan, Theresa and Wolber, Gerhard
and Bermudez, Marcel},
title = {Biased ligands differentially shape the
conformation of the extracellular loop
region in 5-HT2B receptors},
journal = {International Journal of Molecular
Sciences},
volume = {21},
number = {24},
pages = {9728},
note = {Denzinger, Katrin Nguyen, Trung Ngoc
Noonan, Theresa Wolber, Gerhard Bermudez,
Marcel eng 407626949/Deutsche
Forschungsgemeinschaft Switzerland Int J
Mol Sci. 2020 Dec 20;21(24). pii:
ijms21249728. doi: 10.3390/ijms21249728.},
abstract = {G protein-coupled receptors are linked to
various intracellular transducers, each
pathway associated with different
physiological effects. Biased ligands,
capable of activating one pathway over
another, are gaining attention for their
therapeutic potential, as they could
selectively activate beneficial pathways
whilst avoiding those responsible for
adverse effects. We performed molecular
dynamics simulations with known
beta-arrestin-biased ligands like lysergic
acid diethylamide and ergotamine in
complex with the 5-HT2B receptor and
discovered that the extent of ligand bias
is directly connected with the degree of
closure of the extracellular loop region.
Given a loose allosteric coupling of
extracellular and intracellular receptor
regions, we delineate a concept for biased
signaling at serotonin receptors, by which
conformational interference with binding
pocket closure restricts the signaling
repertoire of the receptor. Molecular
docking studies of biased ligands gathered
from the BiasDB demonstrate that larger
ligands only show plausible docking poses
in the ergotamine-bound structure,
highlighting the conformational
constraints associated with bias. This
emphasizes the importance of selecting the
appropriate receptor conformation on which
to base virtual screening workflows in
structure-based drug design of biased
ligands. As this mechanism of ligand bias
has also been observed for muscarinic
receptors, our studies provide a general
mechanism of signaling bias transferable
between aminergic receptors.},
keywords = {Gpcr biased signaling conformational
descriptor drug design molecular dynamics
pharmacophore serotonin receptors virtual
screening},
ISSN = {1422-0067},
DOI = {10.3390/ijms21249728},
url = {https://www.mdpi.com/1422-0067/21/24/9728
https://res.mdpi.com/d_attachment/ijms/ijms-21-09728/article_deploy/ijms-21-09728.pdf},
year = {2020},
type = {Journal Article}
}
x
Biased ligands differentially shape the conformation of the extracellular loop region in 5-HT2B receptors
G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known beta-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.
W. Du, D. Machalz, Q. Yan, E. J. Sorensen, G. Wolber, and M. Bureik. Importance of asparagine-381 and arginine-487 for substrate recognition in CYP4Z1, Biochem Pharmacol, 174:113850, 2020.
Links:
[doi:10.1016/j.bcp.2020.113850]
[show BibTeX]
[show abstract]
x
@article{RN280,
author = {Du, Wei and Machalz, David and Yan, Qi
and Sorensen, Erik J. and Wolber, Gerhard
and Bureik, Matthias},
title = {Importance of asparagine-381 and
arginine-487 for substrate recognition in
CYP4Z1},
journal = {Biochemical Pharmacology},
volume = {174},
pages = {113850},
abstract = {The human cytochrome P450 enzyme CYP4Z1
remains an understudied enzyme despite its
association with poor prognosis and
overexpression in breast cancer. Hence,
CYP4Z1 has previously been suggested as an
anti-breast cancer target. In the present
study we employed extended mutation
analysis to increase our understanding of
the substrate binding mode of this enzyme.
In a combined in vitro and in silico
approach we show for the first time that
residue Arg487 plays an important role in
substrate recognition and binding of
CYP4Z1. Using a large array of recombinant
CYP4Z1 mutants we show that, apart from
Asn381, all other postulated binding
residues only play an auxiliary role in
substrate recognition and binding.
Different substrate interaction motifs
were identified via dynamic pharmacophores
(dynophores) and their impact on
catalytically competent substrate binding
was classified. These new insights on the
substrate recognition and binding mode
represent an important step towards the
rational design of CYP4Z1 prodrugs and
guide further investigations into the so
far poorly understood physiological role
of CYP4Z1.},
keywords = {Breast cancer CYP4Z1 Mutational studies
Molecular modeling Substrate recognition},
ISSN = {0006-2952},
DOI = {10.1016/j.bcp.2020.113850},
url = {http://www.sciencedirect.com/science/article/pii/S000629522030071X},
year = {2020},
type = {Journal Article}
}
x
Importance of asparagine-381 and arginine-487 for substrate recognition in CYP4Z1
The human cytochrome P450 enzyme CYP4Z1 remains an understudied enzyme despite its association with poor prognosis and overexpression in breast cancer. Hence, CYP4Z1 has previously been suggested as an anti-breast cancer target. In the present study we employed extended mutation analysis to increase our understanding of the substrate binding mode of this enzyme. In a combined in vitro and in silico approach we show for the first time that residue Arg487 plays an important role in substrate recognition and binding of CYP4Z1. Using a large array of recombinant CYP4Z1 mutants we show that, apart from Asn381, all other postulated binding residues only play an auxiliary role in substrate recognition and binding. Different substrate interaction motifs were identified via dynamic pharmacophores (dynophores) and their impact on catalytically competent substrate binding was classified. These new insights on the substrate recognition and binding mode represent an important step towards the rational design of CYP4Z1 prodrugs and guide further investigations into the so far poorly understood physiological role of CYP4Z1.
M. Dumitrascuta, M. Bermudez, S. Ballet, G. Wolber, and M. Spetea. Mechanistic understanding of peptide analogues, dalda, [Dmt1]DALDA, and KGOP01, binding to the µ opioid receptor, Molecules, 25(9):2087, 2020.
Links:
[doi:10.3390/molecules25092087]
[show BibTeX]
[show abstract]
x
@article{RN285,
author = {Dumitrascuta, M. and Bermudez, M. and
Ballet, S. and Wolber, G. and Spetea, M.},
title = {Mechanistic understanding of peptide
analogues, dalda, [Dmt1]DALDA, and KGOP01,
binding to the µ opioid receptor},
journal = {Molecules},
volume = {25},
number = {9},
pages = {2087},
note = {Lr4vz Times Cited:2 Cited References
Count:52},
abstract = {The mu opioid receptor (MOR) is the
primary target for analgesia of endogenous
opioid peptides, alkaloids, synthetic
small molecules with diverse scaffolds,
and peptidomimetics. Peptide-based opioids
are viewed as potential analgesics with
reduced side effects and have received
constant scientific interest over the
years. This study focuses on three potent
peptide and peptidomimetic MOR agonists,
DALDA, [Dmt(1)]DALDA, and KGOP01, and the
prototypical peptide MOR agonist DAMGO. We
present the first molecular modeling study
and structure-activity relationships aided
by in vitro assays and molecular docking
of the opioid peptide analogues, in order
to gain insight into their mode of binding
to the MOR. In vitro binding and
functional assays revealed the same rank
order with KGOP01 [Dmt(1)]DALDA DAMGO
DALDA for both binding and MOR
activation. Using molecular docking at the
MOR and three-dimensional interaction
pattern analysis, we have rationalized the
experimental outcomes and highlighted key
amino acid residues responsible for
agonist binding to the MOR. The Dmt (2 ',6
'-dimethyl-L-Tyr) moiety of [Dmt(1)]DALDA
and KGOP01 was found to represent the
driving force for their high potency and
agonist activity at the MOR. These
findings contribute to a deeper
understanding of MOR function and flexible
peptide ligand-MOR interactions, that are
of significant relevance for the future
design of opioid peptide-based
analgesics.},
keywords = {mu opioid receptor opioid peptides and
peptidomimetics damgo dalda [dmt(1)]dalda
kgop01 binding molecular docking
structure-activity relationships in-vitro
potent pharmacology
h-dmt-d-arg-phe-lys-nh2 activation ligands
agonist},
ISSN = {1420-3049 (Electronic) 1420-3049
(Linking)},
DOI = {10.3390/molecules25092087},
url = {Go to ISI://WOS:000535695900083
https://res.mdpi.com/d_attachment/molecules/molecules-25-02087/article_deploy/molecules-25-02087-v2.pdf},
year = {2020},
type = {Journal Article}
}
x
Mechanistic understanding of peptide analogues, dalda, [Dmt1]DALDA, and KGOP01, binding to the µ opioid receptor
The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt(1)]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure-activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt(1)]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2 ',6 '-dimethyl-L-Tyr) moiety of [Dmt(1)]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand-MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.
M. Dumitrascuta, M. Bermudez, T. Ben Haddou, E. Guerrieri, L. Schlafer, A. Ritsch, S. Hosztafi, A. Lantero, C. Kreutz, D. Massotte, H. Schmidhammer, G. Wolber, and M. Spetea. N-phenethyl substitution in 14-methoxy-n-methylmorphinan-6-ones turns selective mu opioid receptor ligands into dual µ/δ opioid receptor agonists, Scientific Reports, 10(1):5653, 2020.
Links:
[doi:10.1038/s41598-020-62530-w]
[show BibTeX]
[show abstract]
x
@article{RN290,
author = {Dumitrascuta, M. and Bermudez, M. and Ben
Haddou, T. and Guerrieri, E. and Schlafer,
L. and Ritsch, A. and Hosztafi, S. and
Lantero, A. and Kreutz, C. and Massotte,
D. and Schmidhammer, H. and Wolber, G. and
Spetea, M.},
title = {N-phenethyl substitution in
14-methoxy-n-methylmorphinan-6-ones turns
selective mu opioid receptor ligands into
dual µ/δ opioid receptor agonists},
journal = {Scientific Reports},
volume = {10},
number = {1},
pages = {5653},
note = {Nb3it Times Cited:1 Cited References
Count:56},
abstract = {Morphine and structurally-derived
compounds are mu opioid receptor (mu OR)
agonists, and the most effective analgesic
drugs. However, their usefulness is
limited by serious side effects, including
dependence and abuse potential. The
N-substituent in morphinans plays an
important role in opioid activities in
vitro and in vivo. This study presents the
synthesis and pharmacological evaluation
of new N-phenethyl substituted
14-O-methylmorphinan-6-ones. Whereas
substitution of the N-methyl substituent
in morphine (1) and oxymorphone (2) by an
N-phenethyl group enhances binding
affinity, selectivity and agonist potency
at the mu OR of 1a and 2a, the N-phenethyl
substitution in
14-methoxy-N-methylmorphinan-6-ones (3 and
4) converts selective mu OR ligands into
dual mu/delta OR agonists (3a and 4a).
Contrary to N-methylmorphinans 1-4, the
N-phenethyl substituted morphinans 1a-4a
produce effective and potent
antinociception without motor impairment
in mice. Using docking and molecular
dynamics simulations with the mu OR, we
establish that N-methylmorphinans 1-4 and
their N-phenethyl counterparts 1a-4a share
several essential receptor-ligand
interactions, but also interaction pattern
differences related to specific structural
features, thus providing a structural
basis for their pharmacological profiles.
The emerged structure-activity
relationships in this class of morphinans
provide important information for tuning
in vitro and in vivo opioid activities
towards discovery of effective and safer
analgesics.},
keywords = {biological evaluation delta-agonists
highly potent 14-alkoxymorphinans
derivatives analgesics 14-methoxymetopon
antagonism tolerance 14-alkoxy},
ISSN = {2045-2322},
DOI = {10.1038/s41598-020-62530-w},
url = {Go to ISI://WOS:000560409100007
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101422/pdf/41598_2020_Article_62530.pdf},
year = {2020},
type = {Journal Article}
}
x
N-phenethyl substitution in 14-methoxy-n-methylmorphinan-6-ones turns selective mu opioid receptor ligands into dual µ/δ opioid receptor agonists
Morphine and structurally-derived compounds are mu opioid receptor (mu OR) agonists, and the most effective analgesic drugs. However, their usefulness is limited by serious side effects, including dependence and abuse potential. The N-substituent in morphinans plays an important role in opioid activities in vitro and in vivo. This study presents the synthesis and pharmacological evaluation of new N-phenethyl substituted 14-O-methylmorphinan-6-ones. Whereas substitution of the N-methyl substituent in morphine (1) and oxymorphone (2) by an N-phenethyl group enhances binding affinity, selectivity and agonist potency at the mu OR of 1a and 2a, the N-phenethyl substitution in 14-methoxy-N-methylmorphinan-6-ones (3 and 4) converts selective mu OR ligands into dual mu/delta OR agonists (3a and 4a). Contrary to N-methylmorphinans 1-4, the N-phenethyl substituted morphinans 1a-4a produce effective and potent antinociception without motor impairment in mice. Using docking and molecular dynamics simulations with the mu OR, we establish that N-methylmorphinans 1-4 and their N-phenethyl counterparts 1a-4a share several essential receptor-ligand interactions, but also interaction pattern differences related to specific structural features, thus providing a structural basis for their pharmacological profiles. The emerged structure-activity relationships in this class of morphinans provide important information for tuning in vitro and in vivo opioid activities towards discovery of effective and safer analgesics.
M. T. Gabr, D. Machalz, S. Pach, and G. Wolber. A benzoxazole derivative as an inhibitor of anaerobic choline metabolism by human gut microbiota, RSC Medicinal Chemistry, 11(12):1402-1412, 2020.
Links:
[doi:10.1039/D0MD00218F]
[show BibTeX]
[show abstract]
x
@article{RN298,
author = {Gabr, Moustafa T. and Machalz, David and
Pach, Szymon and Wolber, Gerhard},
title = {A benzoxazole derivative as an inhibitor
of anaerobic choline metabolism by human
gut microbiota},
journal = {RSC Medicinal Chemistry},
volume = {11},
number = {12},
pages = {1402-1412},
note = {Pg4qx Times Cited:0 Cited References
Count:65},
abstract = {Metabolic pathways mediated by human gut
bacteria have emerged as potential
therapeutic targets because of their
association with the pathophysiology of
various human diseases. The anaerobic
transformation of choline into
trimethylamine (TMA) by gut microbiota is
directly linked to type 2 diabetes, fatty
liver disease, and cardiovascular
diseases. Structural analogs of choline
have been developed as competitive
inhibitors of choline TMA-lyase (CutC), a
key enzyme for the conversion of choline
to TMA. However, weak to moderate CutC
inhibitory profiles of the choline analogs
limit their further advancement into
clinical translation. In this study, we
introduce a glycomimetic-based approach
for the identification of CutC inhibitors
with intestinal metabolic stability. Our
workflow started with screening of a small
library of glycomimetics for metabolic
stability in the presence of human
intestinal S9 fraction. Further screening
using an in vitro CutC inhibitory assay
identified a benzoxazole ligand (BO-I) as
a CutC inhibitor with an IC50 value of 2.4
± 0.3 μM. Kinetic analysis revealed that
BO-I functions as a non-competitive
inhibitor of CutC. Interestingly, BO-I
reduced the production of TMA in whole
cell assays of multiple bacterial strains
as well as in complex biological
environments. Therefore, structural
optimization of BO-I holds promise for the
development of efficient gut
microbiota-targeted small molecules.},
keywords = {trimethylamine n-oxide drug-metabolism
monooxygenase 3 health glycomimetics
chemistry impact lyase fmo3},
DOI = {10.1039/D0MD00218F},
url = {http://dx.doi.org/10.1039/D0MD00218F
https://pubs.rsc.org/en/content/articlepdf/2020/md/d0md00218f},
year = {2020},
type = {Journal Article}
}
x
A benzoxazole derivative as an inhibitor of anaerobic choline metabolism by human gut microbiota
Metabolic pathways mediated by human gut bacteria have emerged as potential therapeutic targets because of their association with the pathophysiology of various human diseases. The anaerobic transformation of choline into trimethylamine (TMA) by gut microbiota is directly linked to type 2 diabetes, fatty liver disease, and cardiovascular diseases. Structural analogs of choline have been developed as competitive inhibitors of choline TMA-lyase (CutC), a key enzyme for the conversion of choline to TMA. However, weak to moderate CutC inhibitory profiles of the choline analogs limit their further advancement into clinical translation. In this study, we introduce a glycomimetic-based approach for the identification of CutC inhibitors with intestinal metabolic stability. Our workflow started with screening of a small library of glycomimetics for metabolic stability in the presence of human intestinal S9 fraction. Further screening using an in vitro CutC inhibitory assay identified a benzoxazole ligand (BO-I) as a CutC inhibitor with an IC50 value of 2.4 ± 0.3 μM. Kinetic analysis revealed that BO-I functions as a non-competitive inhibitor of CutC. Interestingly, BO-I reduced the production of TMA in whole cell assays of multiple bacterial strains as well as in complex biological environments. Therefore, structural optimization of BO-I holds promise for the development of efficient gut microbiota-targeted small molecules.
M. Grabowski, M. Bermudez, T. Rudolf, D. Sribar, P. Varga, M. S. Murgueitio, G. Wolber, J. Rademann, and G. Weindl. Identification and validation of a novel dual small-molecule TLR2/8 antagonist, Biochem Pharmacol, 177:113957, 2020.
Links:
[doi:10.1016/j.bcp.2020.113957]
[show BibTeX]
[show abstract]
x
@article{RN283,
author = {Grabowski, M. and Bermudez, M. and
Rudolf, T. and Sribar, D. and Varga, P.
and Murgueitio, M. S. and Wolber, G. and
Rademann, J. and Weindl, G.},
title = {Identification and validation of a novel
dual small-molecule TLR2/8 antagonist},
journal = {Biochemical Pharmacology},
volume = {177},
pages = {113957},
note = {Lz5eu Times Cited:0 Cited References
Count:61},
abstract = {Toll-like receptor 2 (TLR2) and TLR8 are
involved in the recognition of bacterial
and viral components and are linked not
only to protective antimicrobial immunity
but also to inflammatory diseases.
Recently, increasing attention has been
paid to the receptor crosstalk between
TLR2 and TLR8 to fine-tune innate immune
responses. In this study, we report a
novel dual TLR2/TLR8 antagonist, compound
24 that was developed by a modeling-guided
synthesis approach. The modulator was
optimized from the previously reported
1,3-benzothiazole derivative, compound 8.
Compound 24 was pharmacologically
characterized for the ability to inhibit
TLR2- and TLR8-mediated responses in
TLR-overexpressing reporter cells and
THP-1 macrophages. The modulator showed
high efficacy with IC50, values in the low
micromolar range for both TLR5,
selectivity towards other TLR5 and low
cytotoxicity. At TLR2, a slight
predominance for the TLR2/1 heterodimer
was found in reporter cells selectively
expressing TLR2/1 or TLR2/6 heterodimers.
Concentration ratio analysis in the
presence of Pam(3)CSK(4) or Pam(2)CSK(4)
indicated non-competitive antagonist
behavior at hTLR2. In computational
docking studies, a plausible alternative
binding mode of compound 24 was predicted
for both TLR2 and TLR8. Our results
provide evidence that it is feasible to
simultaneously and selectively target
endosomal- and surface-located TLR5. We
identified a small-molecule dual TLR2/8
antagonist that may serve as a valuable
pharmacological tool to decipher the role
of TLR2/8 co-signaling in inflammation.},
keywords = {drug discovery computer modeling
toll-like receptor (tlr) innate immunity
inflammation virtual screening dual
antagonist non-competitive antagonism
toll-like receptors human monocytes
bacterial rna human tlr8 recognition
polymorphisms cooperation inhibition
mechanisms peptides},
ISSN = {0006-2952},
DOI = {10.1016/j.bcp.2020.113957},
url = {Go to ISI://WOS:000541248000032
https://www.sciencedirect.com/science/article/abs/pii/S0006295220301854?via%3Dihub},
year = {2020},
type = {Journal Article}
}
x
Identification and validation of a novel dual small-molecule TLR2/8 antagonist
Toll-like receptor 2 (TLR2) and TLR8 are involved in the recognition of bacterial and viral components and are linked not only to protective antimicrobial immunity but also to inflammatory diseases. Recently, increasing attention has been paid to the receptor crosstalk between TLR2 and TLR8 to fine-tune innate immune responses. In this study, we report a novel dual TLR2/TLR8 antagonist, compound 24 that was developed by a modeling-guided synthesis approach. The modulator was optimized from the previously reported 1,3-benzothiazole derivative, compound 8. Compound 24 was pharmacologically characterized for the ability to inhibit TLR2- and TLR8-mediated responses in TLR-overexpressing reporter cells and THP-1 macrophages. The modulator showed high efficacy with IC50, values in the low micromolar range for both TLR5, selectivity towards other TLR5 and low cytotoxicity. At TLR2, a slight predominance for the TLR2/1 heterodimer was found in reporter cells selectively expressing TLR2/1 or TLR2/6 heterodimers. Concentration ratio analysis in the presence of Pam(3)CSK(4) or Pam(2)CSK(4) indicated non-competitive antagonist behavior at hTLR2. In computational docking studies, a plausible alternative binding mode of compound 24 was predicted for both TLR2 and TLR8. Our results provide evidence that it is feasible to simultaneously and selectively target endosomal- and surface-located TLR5. We identified a small-molecule dual TLR2/8 antagonist that may serve as a valuable pharmacological tool to decipher the role of TLR2/8 co-signaling in inflammation.
M. Grabowski, M. S. Murgueitio, M. Bermudez, G. Wolber, and G. Weindl. The novel small-molecule antagonist MMG-11 preferentially inhibits TLR2/1 signaling, Biochem Pharmacol, 171:113687, 2020.
Links:
[doi:10.1016/j.bcp.2019.113687]
[show BibTeX]
[show abstract]
x
@article{RN279,
author = {Grabowski, Maria and Murgueitio, Manuela
S. and Bermudez, Marcel and Wolber,
Gerhard and Weindl, Günther},
title = {The novel small-molecule antagonist
MMG-11 preferentially inhibits TLR2/1
signaling},
journal = {Biochemical Pharmacology},
volume = {171},
pages = {113687},
abstract = {Toll-like receptor 2 (TLR2) forms
heterodimers with either TLR1 or TLR6 to
induce protective early inflammatory
responses to pathogen- and
damage-associated molecular patterns.
However, excessive activation is
associated with inflammatory and metabolic
diseases. Several TLR2 antagonists have
been described but pharmacological
characterization is still at an early
stage. Previously, we identified the
potent and selective TLR2 antagonist
MMG-11 by computational modelling and
experimental validation. Here, we
characterized the TLR2 antagonists MMG-11
and CU-CPT22 as well as the TIR-domain
binding TLR2 antagonist C29 in
TLR-overexpressing promoter cells as well
as human and mouse macrophages. In line
with our recent studies, MMG-11 abrogated
pro-inflammatory cytokine secretion and
NF-κB activation induced by different
bacterial TLR2 agonists. MMG-11
preferentially inhibited TLR2/1 signaling
in promoter cells stably expressing TLR2
heterodimers and mouse macrophages.
Furthermore, the TLR2 antagonist blocked
ligand-induced interaction of TLR2 with
MyD88 and reduced MAP kinase and NF-κB
activation. MMG-11 and CU-CPT22 but not
C29 displaced Pam3CSK4 in an indirect
binding assay confirming the competitive
mode of action of MMG-11 and CU-CPT22.
Isobologram analysis revealed additive and
synergistic effects when the
non-competitive antagonist C29 was
combined with the competitive antagonist
MMG-11 or CU-CPT22, respectively. In
conclusion, we provide evidence that
MMG-11 acts as a competitive antagonist
with a predominance for the TLR2/1
heterodimer in human and mouse cells. Our
results also indicate that MMG-11 is a
model compound for studying TLR2
signaling.},
keywords = {Inflammation Innate immunity Toll-like
receptors TLR2 TLR2/1 heterodimer
Competitive antagonist},
ISSN = {0006-2952},
DOI = {10.1016/j.bcp.2019.113687},
year = {2020},
type = {Journal Article}
}
x
The novel small-molecule antagonist MMG-11 preferentially inhibits TLR2/1 signaling
Toll-like receptor 2 (TLR2) forms heterodimers with either TLR1 or TLR6 to induce protective early inflammatory responses to pathogen- and damage-associated molecular patterns. However, excessive activation is associated with inflammatory and metabolic diseases. Several TLR2 antagonists have been described but pharmacological characterization is still at an early stage. Previously, we identified the potent and selective TLR2 antagonist MMG-11 by computational modelling and experimental validation. Here, we characterized the TLR2 antagonists MMG-11 and CU-CPT22 as well as the TIR-domain binding TLR2 antagonist C29 in TLR-overexpressing promoter cells as well as human and mouse macrophages. In line with our recent studies, MMG-11 abrogated pro-inflammatory cytokine secretion and NF-κB activation induced by different bacterial TLR2 agonists. MMG-11 preferentially inhibited TLR2/1 signaling in promoter cells stably expressing TLR2 heterodimers and mouse macrophages. Furthermore, the TLR2 antagonist blocked ligand-induced interaction of TLR2 with MyD88 and reduced MAP kinase and NF-κB activation. MMG-11 and CU-CPT22 but not C29 displaced Pam3CSK4 in an indirect binding assay confirming the competitive mode of action of MMG-11 and CU-CPT22. Isobologram analysis revealed additive and synergistic effects when the non-competitive antagonist C29 was combined with the competitive antagonist MMG-11 or CU-CPT22, respectively. In conclusion, we provide evidence that MMG-11 acts as a competitive antagonist with a predominance for the TLR2/1 heterodimer in human and mouse cells. Our results also indicate that MMG-11 is a model compound for studying TLR2 signaling.
J. Holze, M. Bermudez, E. M. Pfeil, M. Kauk, T. Bödefeld, M. Irmen, C. Matera, C. Dallanoce, M. De Amici, U. Holzgrabe, G. M. König, C. Tränkle, G. Wolber, R. Schrage, K. Mohr, C. Hoffmann, E. Kostenis, and A. Bock. Ligand-specific allosteric coupling controls G-Protein-Coupled receptor signaling, ACS Pharmacology & Translational Science, 3(5):859-867, 2020.
Links:
[doi:10.1021/acsptsci.0c00069]
[show BibTeX]
[show abstract]
x
@article{RN296,
author = {Holze, Janine and Bermudez, Marcel and
Pfeil, Eva Marie and Kauk, Michael and
Bödefeld, Theresa and Irmen, Matthias and
Matera, Carlo and Dallanoce, Clelia and De
Amici, Marco and Holzgrabe, Ulrike and
König, Gabriele Maria and Tränkle,
Christian and Wolber, Gerhard and Schrage,
Ramona and Mohr, Klaus and Hoffmann,
Carsten and Kostenis, Evi and Bock,
Andreas},
title = {Ligand-specific allosteric coupling
controls G-Protein-Coupled receptor
signaling},
journal = {ACS Pharmacology & Translational
Science},
volume = {3},
number = {5},
pages = {859-867},
abstract = {Allosteric coupling describes a
reciprocal process whereby
G-protein-coupled receptors (GPCRs) relay
ligand-induced conformational changes from
the extracellular binding pocket to the
intracellular signaling surface.
Therefore, GPCR activation is sensitive to
both the type of extracellular ligand and
intracellular signaling protein. We
hypothesized that ligand-specific
allosteric coupling may result in
preferential (i.e., biased) engagement of
downstream effectors. However, the
structural basis underlying
ligand-dependent control of this essential
allosteric mechanism is poorly understood.
Here, we show that two sets of extended
muscarinic acetylcholine receptor M1
agonists, which only differ in linker
length, progressively constrain receptor
signaling. We demonstrate that stepwise
shortening of their chemical linker
gradually hampers binding pocket closure,
resulting in divergent coupling to
distinct G-protein families. Our data
provide an experimental strategy for the
design of ligands with selective G-protein
recognition and reveal a potentially
general mechanism of ligand-specific
allosteric coupling.},
DOI = {10.1021/acsptsci.0c00069},
url = {https://doi.org/10.1021/acsptsci.0c00069
https://pubs.acs.org/doi/pdf/10.1021/acsptsci.0c00069},
year = {2020},
type = {Journal Article}
}
x
Ligand-specific allosteric coupling controls G-Protein-Coupled receptor signaling
Allosteric coupling describes a reciprocal process whereby G-protein-coupled receptors (GPCRs) relay ligand-induced conformational changes from the extracellular binding pocket to the intracellular signaling surface. Therefore, GPCR activation is sensitive to both the type of extracellular ligand and intracellular signaling protein. We hypothesized that ligand-specific allosteric coupling may result in preferential (i.e., biased) engagement of downstream effectors. However, the structural basis underlying ligand-dependent control of this essential allosteric mechanism is poorly understood. Here, we show that two sets of extended muscarinic acetylcholine receptor M1 agonists, which only differ in linker length, progressively constrain receptor signaling. We demonstrate that stepwise shortening of their chemical linker gradually hampers binding pocket closure, resulting in divergent coupling to distinct G-protein families. Our data provide an experimental strategy for the design of ligands with selective G-protein recognition and reveal a potentially general mechanism of ligand-specific allosteric coupling.
K. B. Loboda, K. Valjavec, M. Štampar, G. Wolber, B. Žegura, M. Filipič, M. S. Dolenc, and A. Perdih. Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase IIα, Bioorg Chem, 99:103828, 2020.
Links:
[doi:10.1016/j.bioorg.2020.103828]
[show BibTeX]
[show abstract]
x
@article{RN297,
author = {Loboda, Kaja Bergant and Valjavec, Katja
and Štampar, Martina and Wolber, Gerhard
and Žegura, Bojana and Filipič, Metka
and Dolenc, Marija Sollner and Perdih,
Andrej},
title = {Design and synthesis of 3,5-substituted
1,2,4-oxadiazoles as catalytic inhibitors
of human DNA topoisomerase IIα},
journal = {Bioorganic Chemistry},
volume = {99},
pages = {103828},
abstract = {Cancer constitutes a group of diseases
linked to abnormal cell growth that can
potentially spread to other parts of the
body and is one of the most common causes
of death. The molecular motors - DNA
topoisomerases - that enable topological
changes of the DNA molecule are one of the
most established targets of cancer
therapies. Due to known limitations of
established topo II poisons such as
cardiotoxicity, induction of secondary
malignancies and recognized cancer cell
resistance, an emerging group of catalytic
topo II inhibitors attempts to circumvent
these challenges. Currently, this approach
comprises several subgroups of
mechanistically diverse inhibitors, one of
which are compounds that act by binding to
their ATPase domain. In this study we have
designed, synthesized and characterized a
new series of 3,5-substituted
1,2,4-oxadiazoles that act as catalytic
inhibitors of human topo IIα. The
introduction of the substituted rigid
substitutions on the oxadiazole backbone
was intended to enhance the interactions
with the ATP binding site. In the
inhibition assays selected compounds
revealed a new class of catalytic
inhibitors targeting this molecular motor
and showed binding to the isolated topo
IIα ATPase domain. The predicted
inhibitor binding geometries were
evaluated in molecular dynamics
simulations and subsequently dynophore
models were derived, which provided a
deeper insight into molecular recognition
with its macromolecular target. Selected
compounds also displayed in vitro
cytotoxicity on the investigated MCF-7
cancer cell line and did not induce
double-strand breaks (DSB), thus
displaying a mechanism of action diverse
from the topo II poisons also on the
cellular level. The substituted
oxadiazoles thus comprise a chemical class
of interesting compounds that are
synthetically fully amenable for further
optimization to anticancer drugs.},
keywords = {Human DNA topoisomerase IIα Catalytic
inhibitors Drug design Oxadiazoles
Anticancer agents},
ISSN = {0045-2068},
DOI = {10.1016/j.bioorg.2020.103828},
url = {http://www.sciencedirect.com/science/article/pii/S0045206820301218
https://www.sciencedirect.com/science/article/abs/pii/S0045206820301218?via%3Dihub},
year = {2020},
type = {Journal Article}
}
x
Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase IIα
Cancer constitutes a group of diseases linked to abnormal cell growth that can potentially spread to other parts of the body and is one of the most common causes of death. The molecular motors - DNA topoisomerases - that enable topological changes of the DNA molecule are one of the most established targets of cancer therapies. Due to known limitations of established topo II poisons such as cardiotoxicity, induction of secondary malignancies and recognized cancer cell resistance, an emerging group of catalytic topo II inhibitors attempts to circumvent these challenges. Currently, this approach comprises several subgroups of mechanistically diverse inhibitors, one of which are compounds that act by binding to their ATPase domain. In this study we have designed, synthesized and characterized a new series of 3,5-substituted 1,2,4-oxadiazoles that act as catalytic inhibitors of human topo IIα. The introduction of the substituted rigid substitutions on the oxadiazole backbone was intended to enhance the interactions with the ATP binding site. In the inhibition assays selected compounds revealed a new class of catalytic inhibitors targeting this molecular motor and showed binding to the isolated topo IIα ATPase domain. The predicted inhibitor binding geometries were evaluated in molecular dynamics simulations and subsequently dynophore models were derived, which provided a deeper insight into molecular recognition with its macromolecular target. Selected compounds also displayed in vitro cytotoxicity on the investigated MCF-7 cancer cell line and did not induce double-strand breaks (DSB), thus displaying a mechanism of action diverse from the topo II poisons also on the cellular level. The substituted oxadiazoles thus comprise a chemical class of interesting compounds that are synthetically fully amenable for further optimization to anticancer drugs.
S. Pach, T. M. Sarter, R. Yousef, D. Schaller, S. Bergemann, C. Arkona, J. Rademann, C. Nitsche, and G. Wolber. Catching a moving target: comparative modeling of flaviviral NS2B-NS3 reveals small molecule Zika protease inhibitors, ACS Medicinal Chemistry Letters, 11(4):514-520, 2020.
Links:
[doi:10.1021/acsmedchemlett.9b00629]
[show BibTeX]
[show abstract]
x
@article{RN287,
author = {Pach, S. and Sarter, T. M. and Yousef, R.
and Schaller, D. and Bergemann, S. and
Arkona, C. and Rademann, J. and Nitsche,
C. and Wolber, G.},
title = {Catching a moving target: comparative
modeling of flaviviral NS2B-NS3 reveals
small molecule Zika protease inhibitors},
journal = {ACS Medicinal Chemistry Letters},
volume = {11},
number = {4},
pages = {514-520},
note = {Le0gi Times Cited:1 Cited References
Count:48},
abstract = {The pivotal role of viral proteases in
virus replication has already been
successfully exploited in several
antiviral drug design campaigns. However,
no efficient antivirals are currently
available against flaviviral infections.
In this study, we present lead-like small
molecule inhibitors of the Zika Virus
(ZIKV) NS2B-NS3 protease. Since only few
nonpeptide competitive ligands are known,
we take advantage of the high structural
similarity with the West Nile Virus (WNV)
NS2B-NS3 protease. A comparative modeling
approach involving our in-house software
PyRod was employed to systematically
analyze the binding sites and develop
molecular dynamics-based 3D pharmacophores
for virtual screening. The identified
compounds were biochemically characterized
revealing low micromolar affinity for both
ZIKV and WNV proteases. Their lead-like
properties together with rationalized
binding modes represent valuable starting
points for future lead optimization. Since
the NS2B-NS3 protease is highly conserved
among flaviviruses, these compounds may
also drive the development of
pan-flaviviral antiviral drugs.},
keywords = {flavivirus protease inhibitors pyrod 3d
pharmacophores dynophores virus ns3
protease serine-protease in-vitro dengue
identification vaccine mutagenesis
discovery progress ligands},
ISSN = {1948-5875},
DOI = {10.1021/acsmedchemlett.9b00629},
url = {Go to ISI://WOS:000526402700018
https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.9b00629},
year = {2020},
type = {Journal Article}
}
x
Catching a moving target: comparative modeling of flaviviral NS2B-NS3 reveals small molecule Zika protease inhibitors
The pivotal role of viral proteases in virus replication has already been successfully exploited in several antiviral drug design campaigns. However, no efficient antivirals are currently available against flaviviral infections. In this study, we present lead-like small molecule inhibitors of the Zika Virus (ZIKV) NS2B-NS3 protease. Since only few nonpeptide competitive ligands are known, we take advantage of the high structural similarity with the West Nile Virus (WNV) NS2B-NS3 protease. A comparative modeling approach involving our in-house software PyRod was employed to systematically analyze the binding sites and develop molecular dynamics-based 3D pharmacophores for virtual screening. The identified compounds were biochemically characterized revealing low micromolar affinity for both ZIKV and WNV proteases. Their lead-like properties together with rationalized binding modes represent valuable starting points for future lead optimization. Since the NS2B-NS3 protease is highly conserved among flaviviruses, these compounds may also drive the development of pan-flaviviral antiviral drugs.
D. Schaller, D. Sribar, T. Noonan, L. H. Deng, T. N. Nguyen, S. Pach, D. Machalz, M. Bermudez, and G. Wolber. Next generation 3D pharmacophore modeling, Wiley Interdisciplinary Reviews: Computational Molecular Science, 10(4):e1468, 2020.
Links:
[doi:10.1002/wcms.1468]
[show BibTeX]
[show abstract]
x
@article{RN291,
author = {Schaller, D. and Sribar, D. and Noonan,
T. and Deng, L. H. and Nguyen, T. N. and
Pach, S. and Machalz, D. and Bermudez, M.
and Wolber, G.},
title = {Next generation 3D pharmacophore
modeling},
journal = {Wiley Interdisciplinary Reviews:
Computational Molecular Science},
volume = {10},
number = {4},
pages = {e1468},
note = {Mc0lp Times Cited:4 Cited References
Count:111},
abstract = {3D pharmacophore models are
three-dimensional ensembles of chemically
defined interactions of a ligand in its
bioactive conformation. They represent an
elegant way to decipher chemically encoded
ligand information and have therefore
become a valuable tool in drug design. In
this review, we provide an overview on the
basic concept of this method and summarize
key studies for applying 3D pharmacophore
models in virtual screening and
mechanistic studies for protein
functionality. Moreover, we discuss recent
developments in the field. The combination
of 3D pharmacophore models with molecular
dynamics simulations could be a quantum
leap forward since these approaches
consider macromolecule-ligand interactions
as dynamic and therefore show a
physiologically relevant interaction
pattern. Other trends include the
efficient usage of 3D pharmacophore
information in machine learning and
artificial intelligence applications or
freely accessible web servers for 3D
pharmacophore modeling. The recent
developments show that 3D pharmacophore
modeling is a vibrant field with various
applications in drug discovery and beyond.
This article is categorized under:
Computer and Information Science
Chemoinformatics Computer and Information
Science Computer Algorithms and
Programming Molecular and Statistical
Mechanics Molecular Interactions},
keywords = {3d pharmacophores artifical intelligence
machine learning virtual screening web
services competitive saturation silcs drug
discovery dynamics simulations
site-identification covalent inhibitors
chemical space protein binding design
receptor},
ISSN = {1759-0876},
DOI = {10.1002/wcms.1468},
url = {Go to ISI://WOS:000516132600001
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/wcms.1468?download= true},
year = {2020},
type = {Journal Article}
}
x
Next generation 3D pharmacophore modeling
3D pharmacophore models are three-dimensional ensembles of chemically defined interactions of a ligand in its bioactive conformation. They represent an elegant way to decipher chemically encoded ligand information and have therefore become a valuable tool in drug design. In this review, we provide an overview on the basic concept of this method and summarize key studies for applying 3D pharmacophore models in virtual screening and mechanistic studies for protein functionality. Moreover, we discuss recent developments in the field. The combination of 3D pharmacophore models with molecular dynamics simulations could be a quantum leap forward since these approaches consider macromolecule-ligand interactions as dynamic and therefore show a physiologically relevant interaction pattern. Other trends include the efficient usage of 3D pharmacophore information in machine learning and artificial intelligence applications or freely accessible web servers for 3D pharmacophore modeling. The recent developments show that 3D pharmacophore modeling is a vibrant field with various applications in drug discovery and beyond. This article is categorized under: Computer and Information Science > Chemoinformatics Computer and Information Science > Computer Algorithms and Programming Molecular and Statistical Mechanics > Molecular Interactions
D. Schaller, and G. Wolber. Pyrod enables rational homology model-based virtual screening against MCHR1, Mol Inf, 39(6):e2000020, 2020.
Links:
[doi:10.1002/minf.202000020]
[show BibTeX]
[show abstract]
x
@article{RN286,
author = {Schaller, D. and Wolber, G.},
title = {Pyrod enables rational homology
model-based virtual screening against
MCHR1},
journal = {Molecular Informatics},
volume = {39},
number = {6},
pages = {e2000020},
note = {Lv0tp Times Cited:0 Cited References
Count:40},
abstract = {Several encouraging pre-clinical results
highlight the melanin-concentrating
hormone receptor 1 (MCHR1) as promising
target for anti-obesity drug development.
Currently however, experimentally resolved
structures of MCHR1 are not available,
which complicates rational drug design
campaigns. In this study, we aimed at
developing accurate, homologymodel-based
3D pharmacophores against MCHR1. We show
that traditional approaches involving
docking of known active small molecules
are hindered by the flexibility of binding
pocket residues. Instead, we derived
three-dimensional pharmacophores from
molecular dynamics simulations by
employing our novel open-source software
PyRod. In a retrospective evaluation, the
generated 3D pharmacophores were highly
predictive returning up to 35 % of active
molecules and showing an early enrichment
(EF1) of up to 27.6. Furthermore, PyRod
pharmacophores demonstrate higher
sensitivity than ligand-based
pharmacophores and deliver structural
insights, which are key to rational lead
optimization.},
keywords = {mchr1 pyrod 3d pharmacophore homology
modeling md simulation protein dynamics
database ligands system diet},
ISSN = {1868-1743},
DOI = {10.1002/minf.202000020},
url = {Go to ISI://WOS:000529246800001
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317519/pdf/MINF-39-2000020.pdf},
year = {2020},
type = {Journal Article}
}
x
Pyrod enables rational homology model-based virtual screening against MCHR1
Several encouraging pre-clinical results highlight the melanin-concentrating hormone receptor 1 (MCHR1) as promising target for anti-obesity drug development. Currently however, experimentally resolved structures of MCHR1 are not available, which complicates rational drug design campaigns. In this study, we aimed at developing accurate, homologymodel-based 3D pharmacophores against MCHR1. We show that traditional approaches involving docking of known active small molecules are hindered by the flexibility of binding pocket residues. Instead, we derived three-dimensional pharmacophores from molecular dynamics simulations by employing our novel open-source software PyRod. In a retrospective evaluation, the generated 3D pharmacophores were highly predictive returning up to 35 % of active molecules and showing an early enrichment (EF1) of up to 27.6. Furthermore, PyRod pharmacophores demonstrate higher sensitivity than ligand-based pharmacophores and deliver structural insights, which are key to rational lead optimization.
D. Stepanov, S. Canipa, and G. Wolber. HuskinDB, a database for skin permeation of xenobiotics, Scientific Data, 7(1):426, 2020.
Links:
[doi:10.1038/s41597-020-00764-z]
[show BibTeX]
[show abstract]
x
@article{RN294,
author = {Stepanov, Dmitri and Canipa, Steven and
Wolber, Gerhard},
title = {HuskinDB, a database for skin permeation
of xenobiotics},
journal = {Scientific Data},
volume = {7},
number = {1},
pages = {426},
abstract = {Skin permeation is an essential
biological property of small organic
compounds our body is exposed to, such as
drugs in topic formulations, cosmetics,
and environmental toxins. Despite the
limited availability of experimental data,
there is a lack of systematic analysis and
structure. We present a novel resource on
skin permeation data that collects all
measurements available in the literature
and systematically structures experimental
conditions. Besides the skin permeation
value kp, it includes experimental
protocols such as skin source site, skin
layer used, preparation technique, storage
conditions, as well as test conditions
such as temperature, pH as well as the
type of donor and acceptor solution. It is
important to include these parameters in
the assessment of the skin permeation
data. In addition, we provide an analysis
of physicochemical properties and chemical
space coverage, laying the basis for
applicability domain determination of
insights drawn from the collected data
points. The database is freely accessible
under https://huskindb.drug-design.deor
https://doi.org/10.7303/syn21998881.},
ISSN = {2052-4463},
DOI = {10.1038/s41597-020-00764-z},
url = {https://doi.org/10.1038/s41597-020-00764-z
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708619/pdf/41597_2020_Article_764.pdf},
year = {2020},
type = {Journal Article}
}
x
HuskinDB, a database for skin permeation of xenobiotics
Skin permeation is an essential biological property of small organic compounds our body is exposed to, such as drugs in topic formulations, cosmetics, and environmental toxins. Despite the limited availability of experimental data, there is a lack of systematic analysis and structure. We present a novel resource on skin permeation data that collects all measurements available in the literature and systematically structures experimental conditions. Besides the skin permeation value kp, it includes experimental protocols such as skin source site, skin layer used, preparation technique, storage conditions, as well as test conditions such as temperature, pH as well as the type of donor and acceptor solution. It is important to include these parameters in the assessment of the skin permeation data. In addition, we provide an analysis of physicochemical properties and chemical space coverage, laying the basis for applicability domain determination of insights drawn from the collected data points. The database is freely accessible under https://huskindb.drug-design.deor https://doi.org/10.7303/syn21998881.
Y. Sun, D. Machalz, G. Wolber, M. K. Parr, and M. Bureik. Functional expression of all human sulfotransferases in fission yeast, assay development, and structural models for isoforms SULT4A1 and SULT6B1, Biomolecules, 10(11):1517, 2020.
Links:
[doi:10.3390/biom10111517]
[show BibTeX]
x
@article{RN295,
author = {Sun, Yanan and Machalz, David and Wolber,
Gerhard and Parr, Maria Kristina and
Bureik, Matthias},
title = {Functional expression of all human
sulfotransferases in fission yeast, assay
development, and structural models for
isoforms SULT4A1 and SULT6B1},
journal = {Biomolecules},
volume = {10},
number = {11},
pages = {1517},
ISSN = {2218-273X},
DOI = {10.3390/biom10111517},
url = {https://www.mdpi.com/2218-273X/10/11/1517
https://res.mdpi.com/d_attachment/biomolecules/biomolecules-10-01517/article_deploy/biomolecules-10-01517.pdf},
year = {2020},
type = {Journal Article}
}
D. Volpato, M. Kauk, R. Messerer, M. Bermudez, G. Wolber, A. Bock, C. Hoffmann, and U. Holzgrabe. The role of orthosteric building blocks of bitopic ligands for muscarinic M1 receptors, ACS Omega, 5(49):31706-31715, 2020.
Links:
[doi:10.1021/acsomega.0c04220]
[show BibTeX]
[show abstract]
x
@article{RN300,
author = {Volpato, Daniela and Kauk, Michael and
Messerer, Regina and Bermudez, Marcel and
Wolber, Gerhard and Bock, Andreas and
Hoffmann, Carsten and Holzgrabe, Ulrike},
title = {The role of orthosteric building blocks
of bitopic ligands for muscarinic M1
receptors},
journal = {ACS Omega},
volume = {5},
number = {49},
pages = {31706-31715},
abstract = {The muscarinic M1 acetylcholine receptor
is an important drug target for the
treatment of various neurological
disorders. Designing M1 receptor-selective
drugs has proven challenging, mainly due
to the high conservation of the
acetylcholine binding site among
muscarinic receptor subtypes. Therefore,
less conserved and topographically
distinct allosteric binding sites have
been explored to increase M1 receptor
selectivity. In this line, bitopic
ligands, which target orthosteric and
allosteric binding sites simultaneously,
may provide a promising strategy. Here, we
explore the allosteric, M1-selective BQCAd
scaffold derived from BQCA as a starting
point for the design, synthesis, and
pharmacological evaluation of a series of
novel bitopic ligands in which the
orthosteric moieties and linker lengths
are systematically varied. Since
β-arrestin recruitment seems to be
favorable to therapeutic implication, all
the compounds were investigated by G
protein and β-arrestin assays. Some
bitopic ligands are partial to full
agonists for G protein activation, some
activate β-arrestin recruitment, and the
degree of β-arrestin recruitment varies
according to the respective modification.
The allosteric BQCAd scaffold controls the
positioning of the orthosteric ammonium
group of all ligands, suggesting that this
interaction is essential for stimulating G
protein activation. However, β-arrestin
recruitment is not affected. The novel set
of bitopic ligands may constitute a
toolbox to study the requirements of
β-arrestin recruitment during ligand
design for therapeutic usage.},
ISSN = {2470-1343},
DOI = {10.1021/acsomega.0c04220},
url = {https://doi.org/10.1021/acsomega.0c04220
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745449/pdf/ao0c04220.pdf},
year = {2020},
type = {Journal Article}
}
x
The role of orthosteric building blocks of bitopic ligands for muscarinic M1 receptors
The muscarinic M1 acetylcholine receptor is an important drug target for the treatment of various neurological disorders. Designing M1 receptor-selective drugs has proven challenging, mainly due to the high conservation of the acetylcholine binding site among muscarinic receptor subtypes. Therefore, less conserved and topographically distinct allosteric binding sites have been explored to increase M1 receptor selectivity. In this line, bitopic ligands, which target orthosteric and allosteric binding sites simultaneously, may provide a promising strategy. Here, we explore the allosteric, M1-selective BQCAd scaffold derived from BQCA as a starting point for the design, synthesis, and pharmacological evaluation of a series of novel bitopic ligands in which the orthosteric moieties and linker lengths are systematically varied. Since β-arrestin recruitment seems to be favorable to therapeutic implication, all the compounds were investigated by G protein and β-arrestin assays. Some bitopic ligands are partial to full agonists for G protein activation, some activate β-arrestin recruitment, and the degree of β-arrestin recruitment varies according to the respective modification. The allosteric BQCAd scaffold controls the positioning of the orthosteric ammonium group of all ligands, suggesting that this interaction is essential for stimulating G protein activation. However, β-arrestin recruitment is not affected. The novel set of bitopic ligands may constitute a toolbox to study the requirements of β-arrestin recruitment during ligand design for therapeutic usage.
2019 and earlier
[147]
L. Agnetta, M. Bermudez, F. Riefolo, C. Matera, E. Claro, R. Messerer, T. Littmann, G. Wolber, U. Holzgrabe, and M. Decker. Fluorination of photoswitchable muscarinic agonists tunes receptor pharmacology and photochromic properties, J Med Chem, 62(6):3009-3020, 2019.
Links:
[doi:10.1021/acs.jmedchem.8b01822]
[show BibTeX]
x
@article{RN264,
author = {Agnetta, Luca and Bermudez, Marcel and
Riefolo, Fabio and Matera, Carlo and
Claro, Enrique and Messerer, Regina and
Littmann, Timo and Wolber, Gerhard and
Holzgrabe, Ulrike and Decker, Michael},
title = {Fluorination of photoswitchable
muscarinic agonists tunes receptor
pharmacology and photochromic properties},
journal = {Journal of Medicinal Chemistry},
volume = {62},
number = {6},
pages = {3009-3020},
keywords = {gpcr},
ISSN = {0022-2623},
DOI = {10.1021/acs.jmedchem.8b01822},
url = {https://doi.org/10.1021/acs.jmedchem.8b01822
https://pubs.acs.org/doi/pdfplus/10.1021/acs.jmedchem.8b01822},
year = {2019},
type = {Journal Article}
}
H. Aygun Cevher, D. Schaller, M. A. Gandini, O. Kaplan, E. Gambeta, F. X. Zhang, M. Celebier, M. N. Tahir, G. W. Zamponi, G. Wolber, and M. G. Gunduz. Discovery of Michael acceptor containing 1,4-dihydropyridines as first covalent inhibitors of L-/T-type calcium channels, Bioorg Chem, 91:103187, 2019.
Links:
[doi:10.1016/j.bioorg.2019.103187]
[show BibTeX]
[show abstract]
x
@article{RN276,
author = {Aygun Cevher, H. and Schaller, D. and
Gandini, M. A. and Kaplan, O. and Gambeta,
E. and Zhang, F. X. and Celebier, M. and
Tahir, M. N. and Zamponi, G. W. and
Wolber, G. and Gunduz, M. G.},
title = {Discovery of Michael acceptor containing
1,4-dihydropyridines as first covalent
inhibitors of L-/T-type calcium channels},
journal = {Bioorg Chem},
volume = {91},
pages = {103187},
note = {Aygun Cevher, Hande Schaller, David
Gandini, Maria A Kaplan, Ozan Gambeta,
Eder Zhang, Fang Xiong Celebier, Mustafa
Tahir, Muhammad Nawaz Zamponi, Gerald W
Wolber, Gerhard Gunduz, Miyase Gozde eng
Bioorg Chem. 2019 Aug 7;91:103187. doi:
10.1016/j.bioorg.2019.103187.},
abstract = {1,4-Dihydropyridines (DHPs) are an
important class of blockers targeting
different calcium channel subtypes and
have great therapeutic value against
cardiovascular and neurophysiologic
conditions. Here, we present the design of
DHP-based hexahydroquinoline derivatives
as either selective or covalent inhibitors
of calcium channels. These compounds were
synthesized via a modified Hantzsch
reaction under microwave irradiation and
characterized by IR, (1)H NMR, (13)C NMR
and mass spectra. Additionally, the
proposed structure of HM12 was resolved by
single crystal X-ray analysis. The
abilities of the target compounds to block
both L- and T-type calcium channels were
evaluated by utilizing the whole-cell
patch clamp technique. Our results
identified covalent inhibitors of calcium
channels for the first time, which could
be achieved by introducing a Michael
acceptor group into the ester side chain
of the compounds. The proposed covalent
binding between the compounds and the
cysteine amino acid (Cys1492) within the
DHP binding pocket of L-type calcium
channel was supported by docking and
pharmacophore analysis as well as a
glutathione reactivity assay.},
keywords = {Calcium channel blocker Covalent binding
Dihydropyridine Hexahydroquinoline
Molecular modeling Whole-cell patch
clamp},
ISSN = {1090-2120 (Electronic) 0045-2068
(Linking)},
DOI = {10.1016/j.bioorg.2019.103187},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31419643
https://www.sciencedirect.com/science/article/abs/pii/S0045206819309290?via%3Dihub},
year = {2019},
type = {Journal Article}
}
x
Discovery of Michael acceptor containing 1,4-dihydropyridines as first covalent inhibitors of L-/T-type calcium channels
1,4-Dihydropyridines (DHPs) are an important class of blockers targeting different calcium channel subtypes and have great therapeutic value against cardiovascular and neurophysiologic conditions. Here, we present the design of DHP-based hexahydroquinoline derivatives as either selective or covalent inhibitors of calcium channels. These compounds were synthesized via a modified Hantzsch reaction under microwave irradiation and characterized by IR, (1)H NMR, (13)C NMR and mass spectra. Additionally, the proposed structure of HM12 was resolved by single crystal X-ray analysis. The abilities of the target compounds to block both L- and T-type calcium channels were evaluated by utilizing the whole-cell patch clamp technique. Our results identified covalent inhibitors of calcium channels for the first time, which could be achieved by introducing a Michael acceptor group into the ester side chain of the compounds. The proposed covalent binding between the compounds and the cysteine amino acid (Cys1492) within the DHP binding pocket of L-type calcium channel was supported by docking and pharmacophore analysis as well as a glutathione reactivity assay.
M. Bermudez, T. N. Nguyen, C. Omieczynski, and G. Wolber. Strategies for the discovery of biased GPCR ligands, Drug Discov Today, 24(4):1031-1037, 2019.
Links:
[doi:10.1016/j.drudis.2019.02.010]
[show BibTeX]
[show abstract]
x
@article{RN267,
author = {Bermudez, Marcel and Nguyen, Trung Ngoc
and Omieczynski, Christian and Wolber,
Gerhard},
title = {Strategies for the discovery of biased
GPCR ligands},
journal = {Drug Discovery Today},
volume = {24},
number = {4},
pages = {1031-1037},
abstract = {G-protein-coupled receptors (GPCRs)
represent important drug targets with
complex pharmacological characteristics.
Biased signaling represents one important
dimension, describing ligand-dependent
shifts of naturally imprinted signaling
profiles. Because biased GPCR modulators
provide potential therapeutic benefits
including higher efficiencies and reduced
adverse effects, the identification of
such ligands as drug candidates is highly
desirable. This review aims to provide an
overview of the challenges and strategies
in the discovery of biased ligands. We
show different approaches for biased
ligand discovery in the example of
G-protein-biased opioid analgesics and
discuss possibilities to design biased
ligands by targeting extracellular
receptor regions.},
keywords = {gpcr},
ISSN = {1359-6446},
DOI = {10.1016/j.drudis.2019.02.010},
url = {http://www.sciencedirect.com/science/article/pii/S1359644618302186
https://pdf.sciencedirectassets.com/271275/1-s2.0-S1359644619X00057/1-s2.0-S1359644618302186/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJGMEQCIBSuXR284U5c9bmAJSN5zVw47n5M5VTNwrBmGQ8hLXVcAiAWIgoCDAYq%2BrLMnoeOj0gcwMsJ%2BK2%2F2vx37jlwfG9V%2FiraAwhBEAIaDDA1OTAwMzU0Njg2NSIMjEBFMn9jIE9t1XN2KrcDLe7GRG%2FXcw3WEgKV9YXbSGYcHYB2z7r%2B9eRerOT0zpE0wRSFgQ%2FOH9BXlp37MIlzoDaMcVajFKZS8gcJXSICZZRdMHztkVCBW4DNZa%2BJxOwJ1E6Q6vzyyBGsc%2FRoV6Xba79A94ndoN8bYy6WNuplWyrl3mWsK2vv7sI6kqAQYvwZAuSo66P%2FLefOdgACsLXUvDUtMMpSN8TmoE6MAFh%2Fj9u1tN2PHd7Si9U0lR%2BPybWjyQIZhRLaPFiPA459dq%2F0DJYDW6PUXjnBlCqj2pjkDd8G%2FcrPGVCvjIs1dEukqNYRPh9wSQFFAb5Fi0wZV3zG%2F46Hc%2FeUQIprBOrsYtxFvQ1UWxSkaVfuuRD2NfJJC%2FoyWTyuxNmD0bdhukh9A21%2B1W83wJfu%2FecDVcxhN9MqXTDLroqrvl%2BRxWFnb%2BWbs%2B%2FV9bgL2cBI6AFt4X60UAEM%2FPSuYh%2FCMbaK1dtKiQLD4N%2F7kxQrpF%2BWzb6z4YOF5hW%2F4Jm%2BgH%2B0v9v9lego%2FcMGf98VdcRdShnMV0057mzmxPdKDL4AivAyKRRfnHrHbLoO1SdPlc41DKXR%2BjK0GtocjZ5j4aUAxDDnpo7rBTq1AThXMgqWLXhCysjiDb69KUDsmtirRuTrXpezLGPDfxkFp5ofIqWUR9J0yQNBLS%2BqlghqmfiGup4DJm90ED%2Bjr269Tuc2Ri4J0zfr7%2BcI1xixL%2Fy0rAQI30TJNbf1CsDGxfVixVDBG1Fkwa3KlpjjfAGAuGKaiPkPOMJuLo8YTbs28PVbbZSstkpcNX0npq661wJ6SM3c0BNDLzt2HCCzsKCoWT8MzDtnFnmY8Er2Z7ayg87lxx0%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090852Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYZNRZYJFV%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=7f58eff199562319314a001e9580c09f4398c03f423e7fcb0c77abbe9f6e7b3f&hash=2eec85bc780a8441b8c56fa4d0c26581dfbc0117ea28d1b8a83af57b9cc39829&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S1359644618302186&tid=spdf-e17f4a4a-0e0c-4d81-94e3-c8ec97d2a8a8&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2019},
type = {Journal Article}
}
x
Strategies for the discovery of biased GPCR ligands
G-protein-coupled receptors (GPCRs) represent important drug targets with complex pharmacological characteristics. Biased signaling represents one important dimension, describing ligand-dependent shifts of naturally imprinted signaling profiles. Because biased GPCR modulators provide potential therapeutic benefits including higher efficiencies and reduced adverse effects, the identification of such ligands as drug candidates is highly desirable. This review aims to provide an overview of the challenges and strategies in the discovery of biased ligands. We show different approaches for biased ligand discovery in the example of G-protein-biased opioid analgesics and discuss possibilities to design biased ligands by targeting extracellular receptor regions.
P. Durairaj, L. Fan, D. Machalz, G. Wolber, and M. Bureik. Functional characterization and mechanistic modeling of the human cytochrome P450 enzyme CYP4A22, Febs Lett, 593(16):2214-2225, 2019.
Links:
[doi:10.1002/1873-3468.13489]
[show BibTeX]
[show abstract]
x
@article{RN275,
author = {Durairaj, Pradeepraj and Fan, Linbing and
Machalz, David and Wolber, Gerhard and
Bureik, Matthias},
title = {Functional characterization and
mechanistic modeling of the human
cytochrome P450 enzyme CYP4A22},
journal = {FEBS Letters},
volume = {593},
number = {16},
pages = {2214-2225},
abstract = {The human cytochrome P450 (CYP) enzyme
CYP4A22 is an orphan CYP with unknown
function. Here, through functional
expression in fission yeast, we show that
CYP4A22 catalyzes fatty acid hydroxylation
as well as aliphatic or aromatic
hydroxylations of luciferin-based probe
substrates. Mechanistic molecular modeling
of CYP4A22 suggests that its
ω-hydroxylation activity is hampered by a
more spacious active site compared to
CYP4B1. Substrate recognition via
side-chains R96 and R233 is indicated by
dynamic three-dimensional pharmacophores
(dynophores) derived from molecular
dynamics simulations. CYP4A22 activity is
inhibited by three unspecific CYP
inhibitors. A comparison of CYP4A22*1 (the
reference standard sequence) with
CYP4A22-WT (the most common allele)
revealed that for the four substrates
tested the WT-enzyme always had lower
activity.},
ISSN = {0014-5793},
DOI = {10.1002/1873-3468.13489},
url = {https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1873-3468.13489
https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/1873-3468.13489},
year = {2019},
type = {Journal Article}
}
x
Functional characterization and mechanistic modeling of the human cytochrome P450 enzyme CYP4A22
The human cytochrome P450 (CYP) enzyme CYP4A22 is an orphan CYP with unknown function. Here, through functional expression in fission yeast, we show that CYP4A22 catalyzes fatty acid hydroxylation as well as aliphatic or aromatic hydroxylations of luciferin-based probe substrates. Mechanistic molecular modeling of CYP4A22 suggests that its ω-hydroxylation activity is hampered by a more spacious active site compared to CYP4B1. Substrate recognition via side-chains R96 and R233 is indicated by dynamic three-dimensional pharmacophores (dynophores) derived from molecular dynamics simulations. CYP4A22 activity is inhibited by three unspecific CYP inhibitors. A comparison of CYP4A22*1 (the reference standard sequence) with CYP4A22-WT (the most common allele) revealed that for the four substrates tested the WT-enzyme always had lower activity.
A. Nass, D. Schaller, and G. Wolber. Assessment of flexible shape complementarity: New opportunities to explain and induce selectivity in ligands of protein tyrosine phosphatase 1B, Mol Inf, 38(5):1800141, 2019.
Links:
[doi:10.1002/minf.201800141]
[show BibTeX]
[show abstract]
x
@article{RN268,
author = {Nass, A. and Schaller, D. and Wolber,
G.},
title = {Assessment of flexible shape
complementarity: New opportunities to
explain and induce selectivity in ligands
of protein tyrosine phosphatase 1B},
journal = {Molecular Informatics},
volume = {38},
number = {5},
pages = {1800141},
note = {Nass, Alexandra Schaller, David Wolber,
Gerhard eng Elsa-Neumann-Foundation
Germany Mol Inform. 2019 Feb 6. doi:
10.1002/minf.201800141.},
abstract = {For drug design projects it is essential
to rationally induce and explain
selectivity. In this context shape
complementarity as well as protein and
ligand flexibility represent important
factors. Currently available tools for the
analysis of protein-ligand interactions
focus mainly on electrostatic
complementarity and/or static structures.
Here we address the shortcomings of
available methods by presenting two new
tools: The first one can be used to assess
steric complementarity in flexible
protein-ligand complexes in order to
explain selectivity of known ligands. It
further allows to determine ligand atoms
with especially good or bad shape-fit
which can be of use in lead optimization
projects. The second tool was designed to
detect differences in protein flexibility
in similar proteins along with their
exploitation for virtual screening. Both
tools yield interesting results when
applied to data of protein tyrosine
phosphatase 1B (PTP1B): The case of PTP1B
has proven especially difficult in terms
of selectivity, due to a closely related
phosphatase connected to severe undesired
effects. With our tool for steric
complementarity assessment we were able to
explain previously undisclosed causes of
moderate selectivity of selected PTP1B
ligands. The second tool allowed us to
find differences of flexibility in the two
highly similar proteins and give
directions for exploitation in virtual
screening.},
keywords = {Computational chemistry Molecular
dynamics Molecular modeling Selectivity
Shape complementarity},
ISSN = {1868-1751 (Electronic) 1868-1743
(Linking)},
DOI = {10.1002/minf.201800141},
url = {https://www.ncbi.nlm.nih.gov/pubmed/30725529
https://onlinelibrary.wiley.com/doi/pdf/10.1002/minf.201800141},
year = {2019},
type = {Journal Article}
}
x
Assessment of flexible shape complementarity: New opportunities to explain and induce selectivity in ligands of protein tyrosine phosphatase 1B
For drug design projects it is essential to rationally induce and explain selectivity. In this context shape complementarity as well as protein and ligand flexibility represent important factors. Currently available tools for the analysis of protein-ligand interactions focus mainly on electrostatic complementarity and/or static structures. Here we address the shortcomings of available methods by presenting two new tools: The first one can be used to assess steric complementarity in flexible protein-ligand complexes in order to explain selectivity of known ligands. It further allows to determine ligand atoms with especially good or bad shape-fit which can be of use in lead optimization projects. The second tool was designed to detect differences in protein flexibility in similar proteins along with their exploitation for virtual screening. Both tools yield interesting results when applied to data of protein tyrosine phosphatase 1B (PTP1B): The case of PTP1B has proven especially difficult in terms of selectivity, due to a closely related phosphatase connected to severe undesired effects. With our tool for steric complementarity assessment we were able to explain previously undisclosed causes of moderate selectivity of selected PTP1B ligands. The second tool allowed us to find differences of flexibility in the two highly similar proteins and give directions for exploitation in virtual screening.
M. J. Ojeda-Montes, A. Casanova-Marti, A. Gimeno, S. Tomas-Hernandez, A. Cereto-Massague, G. Wolber, R. Beltran-Debon, C. Valls, M. Mulero, M. Pinent, G. Pujadas, and S. Garcia-Vallve. Mining large databases to find new leads with low similarity to known actives: application to find new DPP-IV inhibitors, Future Medicinal Chemistry, 11(12):1387-1401, 2019.
Links:
[doi:10.4155/fmc-2018-0597]
[show BibTeX]
[show abstract]
x
@article{RN272,
author = {Ojeda-Montes, M. J. and Casanova-Marti,
A. and Gimeno, A. and Tomas-Hernandez, S.
and Cereto-Massague, A. and Wolber, G. and
Beltran-Debon, R. and Valls, C. and
Mulero, M. and Pinent, M. and Pujadas, G.
and Garcia-Vallve, S.},
title = {Mining large databases to find new leads
with low similarity to known actives:
application to find new DPP-IV
inhibitors},
journal = {Future Medicinal Chemistry},
volume = {11},
number = {12},
pages = {1387-1401},
note = {Ojeda-Montes, Maria J Casanova-Marti,
Angela Gimeno, Aleix Tomas-Hernandez,
Sarah Cereto-Massague, Adria Wolber,
Gerhard Beltran-Debon, Raul Valls,
Cristina Mulero, Miquel Pinent, Montserrat
Pujadas, Gerard Garcia-Vallve, Santiago
eng England Future Med Chem. 2019
Jun;11(12):1387-1401. doi:
10.4155/fmc-2018-0597. Epub 2019 Jul 12.},
abstract = {Aim: Fragment-based drug design or
bioisosteric replacement is used to find
new actives with low (or no) similarity to
existing ones but requires the synthesis
of nonexisting compounds to prove their
predicted bioactivity. Protein-ligand
docking or pharmacophore screening are
alternatives but they can become
computationally expensive when applied to
very large databases such as ZINC.
Therefore, fast strategies are necessary
to find new leads in such databases.
Materials & methods: We designed a
computational strategy to find lead
molecules with very low (or no) similarity
to existing actives and applied it to
DPP-IV. Results: The bioactivity assays
confirm that this strategy finds new leads
for DPP-IV inhibitors. Conclusion: This
computational strategy reduces the time of
finding new lead molecules.},
keywords = {Cd26 dipeptidyl peptidase 4 diversifying
molecular scaffolds expanding chemical
space molecular fingerprints virtual
molecular libraries virtual screening},
ISSN = {1756-8927 (Electronic) 1756-8919
(Linking)},
DOI = {10.4155/fmc-2018-0597},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31298576},
year = {2019},
type = {Journal Article}
}
x
Mining large databases to find new leads with low similarity to known actives: application to find new DPP-IV inhibitors
Aim: Fragment-based drug design or bioisosteric replacement is used to find new actives with low (or no) similarity to existing ones but requires the synthesis of nonexisting compounds to prove their predicted bioactivity. Protein-ligand docking or pharmacophore screening are alternatives but they can become computationally expensive when applied to very large databases such as ZINC. Therefore, fast strategies are necessary to find new leads in such databases. Materials & methods: We designed a computational strategy to find lead molecules with very low (or no) similarity to existing actives and applied it to DPP-IV. Results: The bioactivity assays confirm that this strategy finds new leads for DPP-IV inhibitors. Conclusion: This computational strategy reduces the time of finding new lead molecules.
R. Ottanà, P. Paoli, G. Lori, I. Adornato, S. Previti, A. Naß, G. Wolber, and R. Maccari. Design and evaluation of non-carboxylate 5-arylidene-2-thioxo-4-imidazolidinones as novel non-competitive inhibitors of protein tyrosine phosphatase 1B, Bioorg Chem, 92:103211, 2019.
Links:
[doi:10.1016/j.bioorg.2019.103211]
[show BibTeX]
[show abstract]
x
@article{RN278,
author = {Ottanà, Rosaria and Paoli, Paolo and
Lori, Giulia and Adornato, Ilenia and
Previti, Santo and Naß, Alexandra and
Wolber, Gerhard and Maccari, Rosanna},
title = {Design and evaluation of non-carboxylate
5-arylidene-2-thioxo-4-imidazolidinones as
novel non-competitive inhibitors of
protein tyrosine phosphatase 1B},
journal = {Bioorganic Chemistry},
volume = {92},
pages = {103211},
abstract = {Protein tyrosine phosphatase 1B (PTP1B)
acts as a negative regulator of insulin
and leptin signalling and is crucially
involved in the development of type 2
diabetes mellitus, obesity, cancer and
neurodegenerative diseases. Pursuing our
efforts to identify PTP1B inhibitors
endowed with drug-like properties, we
designed and evaluated
3-aryl-5-arylidene-2-thioxo-4-imidazolidinones
(7) as a novel class of non-carboxylate
PTP1B inhibitors. In agreement with our
design, kinetic studies demonstrated that
selected compounds 7 act as reversible,
non-competitive inhibitors of the target
enzyme at low micromolar concentrations.
Accordingly, molecular docking experiments
suggested that these inhibitors can fit an
allosteric site of PTP1B that we
previously individuated. Moreover,
cellular assays demonstrated that compound
7e acts as a potent insulin-sensitizing
agent in human liver HepG2 cells. Taken
together, our results showed that these
non-competitive PTP1B inhibitors can be
considered promising lead compounds aimed
to enhance druggability of the target
enzyme and identify novel antidiabetic
drugs.},
keywords = {3-aryl-5-arylidene-2-thioxo-4-imidazolidinones
Protein tyrosine phosphatase 1B
Non-competitive inhibitors
Insulin-sensitizing agents Cellular
assays},
ISSN = {00452068},
DOI = {10.1016/j.bioorg.2019.103211},
url = {http://www.sciencedirect.com/science/article/pii/S0045206819307990
https://www.sciencedirect.com/science/article/abs/pii/S0045206819307990?via%3Dihub},
year = {2019},
type = {Journal Article}
}
x
Design and evaluation of non-carboxylate 5-arylidene-2-thioxo-4-imidazolidinones as novel non-competitive inhibitors of protein tyrosine phosphatase 1B
Protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of insulin and leptin signalling and is crucially involved in the development of type 2 diabetes mellitus, obesity, cancer and neurodegenerative diseases. Pursuing our efforts to identify PTP1B inhibitors endowed with drug-like properties, we designed and evaluated 3-aryl-5-arylidene-2-thioxo-4-imidazolidinones (7) as a novel class of non-carboxylate PTP1B inhibitors. In agreement with our design, kinetic studies demonstrated that selected compounds 7 act as reversible, non-competitive inhibitors of the target enzyme at low micromolar concentrations. Accordingly, molecular docking experiments suggested that these inhibitors can fit an allosteric site of PTP1B that we previously individuated. Moreover, cellular assays demonstrated that compound 7e acts as a potent insulin-sensitizing agent in human liver HepG2 cells. Taken together, our results showed that these non-competitive PTP1B inhibitors can be considered promising lead compounds aimed to enhance druggability of the target enzyme and identify novel antidiabetic drugs.
D. Schaller, S. Hagenow, H. Stark, and G. Wolber. Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands, Plos One, 14(6):e0218820, 2019.
Links:
[doi:10.1371/journal.pone.0218820]
[show BibTeX]
[show abstract]
x
@article{RN274,
author = {Schaller, D. and Hagenow, S. and Stark,
H. and Wolber, G.},
title = {Ligand-guided homology modeling drives
identification of novel histamine H3
receptor ligands},
journal = {PLoS One},
volume = {14},
number = {6},
pages = {e0218820},
note = {Schaller, David Hagenow, Stefanie Stark,
Holger Wolber, Gerhard eng PLoS One. 2019
Jun 25;14(6):e0218820. doi:
10.1371/journal.pone.0218820. eCollection
2019.},
abstract = {In this study, we report a ligand-guided
homology modeling approach allowing the
analysis of relevant binding site residue
conformations and the identification of
two novel histamine H3 receptor ligands
with binding affinity in the nanomolar
range. The newly developed method is based
on exploiting an essential charge
interaction characteristic for aminergic
G-protein coupled receptors for ranking 3D
receptor models appropriate for the
discovery of novel compounds through
virtual screening.},
ISSN = {1932-6203 (Electronic) 1932-6203
(Linking)},
DOI = {10.1371/journal.pone.0218820},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31237914
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592549/pdf/pone.0218820.pdf},
year = {2019},
type = {Journal Article}
}
x
Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands
In this study, we report a ligand-guided homology modeling approach allowing the analysis of relevant binding site residue conformations and the identification of two novel histamine H3 receptor ligands with binding affinity in the nanomolar range. The newly developed method is based on exploiting an essential charge interaction characteristic for aminergic G-protein coupled receptors for ranking 3D receptor models appropriate for the discovery of novel compounds through virtual screening.
D. Schaller, S. Pach, and G. Wolber. PyRod: Tracing water molecules in molecular dynamics simulations, J Chem Inf Model, 59(6):2818-2829, 2019.
Links:
[doi:10.1021/acs.jcim.9b00281]
[show BibTeX]
[show abstract]
x
@article{RN270,
author = {Schaller, D. and Pach, S. and Wolber,
G.},
title = {PyRod: Tracing water molecules in
molecular dynamics simulations},
journal = {Journal of Chemical Information and
Modeling},
volume = {59},
number = {6},
pages = {2818-2829},
note = {Schaller, David Pach, Szymon Wolber,
Gerhard eng J Chem Inf Model. 2019 Jun
24;59(6):2818-2829. doi:
10.1021/acs.jcim.9b00281. Epub 2019 May
30.},
abstract = {Ligands entering a protein binding pocket
essentially compete with water molecules
for binding to the protein. Hence, the
location and thermodynamic properties of
water molecules in protein structures have
gained increased attention in the drug
design community. Including corresponding
data into 3D pharmacophore modeling is
essential for efficient high throughput
virtual screening. Here, we present PyRod,
a free and open-source Python software
that allows for visualization of
pharmacophoric binding pocket
characteristics, identification of hot
spots for ligand binding, and subsequent
generation of pharmacophore features for
virtual screening. The implemented
routines analyze the protein environment
of water molecules in molecular dynamics
(MD) simulations and can differentiate
between hydrogen bonded waters as well as
waters in a protein environment of
hydrophobic, charged, or aromatic atom
groups. The gathered information is
further processed to generate dynamic
molecular interaction fields (dMIFs) for
visualization and pharmacophoric features
for virtual screening. The described
software was applied to 5 therapeutically
relevant drug targets, and generated
pharmacophores were evaluated using DUD-E
benchmarking sets. The best performing
pharmacophore was found for the HIV1
protease with an early enrichment factor
of 54.6. PyRod adds a new perspective to
structure-based screening campaigns by
providing easy-to-interpret dMIFs and
purely protein-based pharmacophores that
are solely based on tracing water
molecules in MD simulations. Since
structural information about
cocrystallized ligands is not needed,
screening campaigns can be followed, for
which less or no ligand information is
available. PyRod is freely available at
https://github.com/schallerdavid/pyrod .},
keywords = {software},
ISSN = {1549-960X (Electronic) 1549-9596
(Linking)},
DOI = {10.1021/acs.jcim.9b00281},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31117512},
year = {2019},
type = {Journal Article}
}
x
PyRod: Tracing water molecules in molecular dynamics simulations
Ligands entering a protein binding pocket essentially compete with water molecules for binding to the protein. Hence, the location and thermodynamic properties of water molecules in protein structures have gained increased attention in the drug design community. Including corresponding data into 3D pharmacophore modeling is essential for efficient high throughput virtual screening. Here, we present PyRod, a free and open-source Python software that allows for visualization of pharmacophoric binding pocket characteristics, identification of hot spots for ligand binding, and subsequent generation of pharmacophore features for virtual screening. The implemented routines analyze the protein environment of water molecules in molecular dynamics (MD) simulations and can differentiate between hydrogen bonded waters as well as waters in a protein environment of hydrophobic, charged, or aromatic atom groups. The gathered information is further processed to generate dynamic molecular interaction fields (dMIFs) for visualization and pharmacophoric features for virtual screening. The described software was applied to 5 therapeutically relevant drug targets, and generated pharmacophores were evaluated using DUD-E benchmarking sets. The best performing pharmacophore was found for the HIV1 protease with an early enrichment factor of 54.6. PyRod adds a new perspective to structure-based screening campaigns by providing easy-to-interpret dMIFs and purely protein-based pharmacophores that are solely based on tracing water molecules in MD simulations. Since structural information about cocrystallized ligands is not needed, screening campaigns can be followed, for which less or no ligand information is available. PyRod is freely available at https://github.com/schallerdavid/pyrod .
S. Schramm, L. Agnetta, M. Bermudez, H. Gerwe, M. Irmen, J. Holze, T. Littmann, G. Wolber, C. Trankle, and M. Decker. Novel BQCA- and TBPB-derived M1 receptor hybrid ligands: Orthosteric carbachol differentially regulates partial agonism, ChemMedChem, 14(14):1349-1358, 2019.
Links:
[doi:10.1002/cmdc.201900283]
[show BibTeX]
[show abstract]
x
@article{RN269,
author = {Schramm, S. and Agnetta, L. and Bermudez,
M. and Gerwe, H. and Irmen, M. and Holze,
J. and Littmann, T. and Wolber, G. and
Trankle, C. and Decker, M.},
title = {Novel BQCA- and TBPB-derived M1 receptor
hybrid ligands: Orthosteric carbachol
differentially regulates partial agonism},
journal = {ChemMedChem},
volume = {14},
number = {14},
pages = {1349-1358},
note = {Schramm, Simon Agnetta, Luca Bermudez,
Marcel Gerwe, Hubert Irmen, Matthias
Holze, Janine Littmann, Timo Wolber,
Gerhard Trankle, Christian Decker, Michael
eng International Doctoral program
"Receptor Dynamics"/Elitenetzwerk Bayern
Germany ChemMedChem. 2019 Jul
17;14(14):1349-1358. doi:
10.1002/cmdc.201900283. Epub 2019 Jul 3.},
abstract = {Recently, investigations of the complex
mechanisms of allostery have led to a
deeper understanding of G protein-coupled
receptor (GPCR) activation and signaling
processes. In this context, muscarinic
acetylcholine receptors (mAChRs) are
highly relevant due to their exemplary
role in the study of allosteric
modulation. In this work, we compare and
discuss two sets of putatively dualsteric
ligands, which were designed to connect
carbachol to different types of allosteric
ligands. We chose derivatives of TBPB
[1-(1'-(2-tolyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]
as M1 -selective putative bitopic ligands,
and derivatives of benzyl quinolone
carboxylic acid (BQCA) as an M1 positive
allosteric modulator, varying the distance
between the allosteric and orthosteric
building blocks. Luciferase protein
complementation assays demonstrated that
linker length must be carefully chosen to
yield either agonist or antagonist
behavior. These findings may help to
design biased signaling and/or different
extents of efficacy.},
keywords = {GPCRs allostery dualsteric ligands
muscarinic receptors partial agonists},
ISSN = {1860-7187 (Electronic) 1860-7179
(Linking)},
DOI = {10.1002/cmdc.201900283},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31166078
https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201900283},
year = {2019},
type = {Journal Article}
}
x
Novel BQCA- and TBPB-derived M1 receptor hybrid ligands: Orthosteric carbachol differentially regulates partial agonism
Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1'-(2-tolyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1 -selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.
D. Sribar, M. Grabowski, M. S. Murgueitio, M. Bermudez, G. Weindl, and G. Wolber. Identification and characterization of a novel chemotype for human TLR8 inhibitors, Eur J Med Chem, 179:744-752, 2019.
Links:
[doi:10.1016/j.ejmech.2019.06.084]
[show BibTeX]
[show abstract]
x
@article{RN273,
author = {Sribar, D. and Grabowski, M. and
Murgueitio, M. S. and Bermudez, M. and
Weindl, G. and Wolber, G.},
title = {Identification and characterization of a
novel chemotype for human TLR8
inhibitors},
journal = {European Journal of Medicinal Chemistry},
volume = {179},
pages = {744-752},
note = {Sribar, Dora Grabowski, Maria Murgueitio,
Manuela S Bermudez, Marcel Weindl, Gunther
Wolber, Gerhard eng France Eur J Med Chem.
2019 Jun 29;179:744-752. doi:
10.1016/j.ejmech.2019.06.084.},
abstract = {The endosomal Toll-like receptor 8 (TLR8)
recognizes single-stranded RNA and
initiates early inflammatory responses.
Despite the importance of endosomal TLRs
for human host defense against microbial
pathogens, extensive activation may
contribute to autoimmune and inflammatory
diseases. In contrast to the recent
progress made in the development of
modulators of plasma membrane-bound TLRs,
little is known about endosomal TLR
modulation and very few TLR8 inhibitors
have been reported. In this study, we
discovered and validated novel
small-molecule TLR8 inhibitors. Fourteen
potential TLR8 modulators were
experimentally validated in HEK293T cells
stably overexpressing human TLR8 and THP-1
macrophages. Five compounds inhibited
TLR8-mediated signaling, representing a
hit rate of 36%. The three most potent
compounds neither cause cellular toxicity
nor inhibition of TLR signaling induced by
other receptor subtypes. Conclusively, we
experimentally confirm novel and
selective, pyrimidine-based TLR8
inhibitors with low cytotoxicity that are
relevant candidates for lead optimization
and further mechanistic studies.},
keywords = {Inflammation Inhibitors Pyrimidine
scaffold Toll-like receptor 8 Virtual
screening},
ISSN = {1768-3254 (Electronic) 0223-5234
(Linking)},
DOI = {10.1016/j.ejmech.2019.06.084},
year = {2019},
type = {Journal Article}
}
x
Identification and characterization of a novel chemotype for human TLR8 inhibitors
The endosomal Toll-like receptor 8 (TLR8) recognizes single-stranded RNA and initiates early inflammatory responses. Despite the importance of endosomal TLRs for human host defense against microbial pathogens, extensive activation may contribute to autoimmune and inflammatory diseases. In contrast to the recent progress made in the development of modulators of plasma membrane-bound TLRs, little is known about endosomal TLR modulation and very few TLR8 inhibitors have been reported. In this study, we discovered and validated novel small-molecule TLR8 inhibitors. Fourteen potential TLR8 modulators were experimentally validated in HEK293T cells stably overexpressing human TLR8 and THP-1 macrophages. Five compounds inhibited TLR8-mediated signaling, representing a hit rate of 36%. The three most potent compounds neither cause cellular toxicity nor inhibition of TLR signaling induced by other receptor subtypes. Conclusively, we experimentally confirm novel and selective, pyrimidine-based TLR8 inhibitors with low cytotoxicity that are relevant candidates for lead optimization and further mechanistic studies.
A. Stoll, S. Loke, J. F. Joseph, D. Machalz, X. de la Torre, F. Botrè, G. Wolber, M. Bureik, and M. K. Parr. Fine-mapping of the substrate specificity of human steroid 21-hydroxylase (CYP21A2), J Steroid Biochem, 194:105446, 2019.
Links:
[doi:10.1016/j.jsbmb.2019.105446]
[show BibTeX]
[show abstract]
x
@article{RN277,
author = {Stoll, Anna and Loke, Steffen and Joseph,
Jan Felix and Machalz, David and de la
Torre, Xavier and Botrè, Francesco and
Wolber, Gerhard and Bureik, Matthias and
Parr, Maria Kristina},
title = {Fine-mapping of the substrate specificity
of human steroid 21-hydroxylase
(CYP21A2)},
journal = {Journal of Steroid Biochemistry and
Molecular Biology},
volume = {194},
pages = {105446},
abstract = {Cytochrome P450 enzymes (CYPs) are
capable of catalyzing regio- and
stereo-specific oxy functionalization
reactions which otherwise are major
challenges in organic chemistry. In order
to make the best possible use of these
biocatalysts it is imperative to
understand their specificities. Human
CYP21A2 (steroid 21-hydroxylase) acts on
the side-chain attached to C-17 in ring D
of a steroid substrate, but the
configuration of ring A also plays a
prominent role in substrate cognition.
Here, we comprehensively investigated this
relationship using sixteen
17,17-dimethyl-18-nor-13-ene steroids with
different arrangements of hydroxy-, oxo-,
fluoro- and chloro-groups and in the
presence or absence of double bonds (Δ1
and/or Δ4) and heteroatoms in ring A. The
results show that presence of a 3-oxo
group is a strict requirement for a
CYP21A2 substrate, while the other
configurations tested were all tolerated.
This was also confirmed by control
experiments using endogenous steroids.
While progesterone and
17-hydroxyprogesterone were hydroxylated
at C-21, (17-hydroxy-) pregnenolone did
not react. Molecular docking experiments
indicate that the interaction of the
carbonyl group at C-3 to the side-chain
Arg234 of the enzyme is indispensable.},
keywords = {Cytochrome P450 Fission yeast Gas
chromatography mass spectrometry (GCMS)
Oral turinabol long-term metabolite
Molecular modeling Steroid hydroxylation},
ISSN = {0960-0760},
DOI = {10.1016/j.jsbmb.2019.105446},
url = {http://www.sciencedirect.com/science/article/pii/S0960076019304169
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year = {2019},
type = {Journal Article}
}
x
Fine-mapping of the substrate specificity of human steroid 21-hydroxylase (CYP21A2)
Cytochrome P450 enzymes (CYPs) are capable of catalyzing regio- and stereo-specific oxy functionalization reactions which otherwise are major challenges in organic chemistry. In order to make the best possible use of these biocatalysts it is imperative to understand their specificities. Human CYP21A2 (steroid 21-hydroxylase) acts on the side-chain attached to C-17 in ring D of a steroid substrate, but the configuration of ring A also plays a prominent role in substrate cognition. Here, we comprehensively investigated this relationship using sixteen 17,17-dimethyl-18-nor-13-ene steroids with different arrangements of hydroxy-, oxo-, fluoro- and chloro-groups and in the presence or absence of double bonds (Δ1 and/or Δ4) and heteroatoms in ring A. The results show that presence of a 3-oxo group is a strict requirement for a CYP21A2 substrate, while the other configurations tested were all tolerated. This was also confirmed by control experiments using endogenous steroids. While progesterone and 17-hydroxyprogesterone were hydroxylated at C-21, (17-hydroxy-) pregnenolone did not react. Molecular docking experiments indicate that the interaction of the carbonyl group at C-3 to the side-chain Arg234 of the enzyme is indispensable.
N. K. Wenke, J. Kreye, E. Andrzejak, A. van Casteren, J. Leubner, M. S. Murgueitio, S. M. Reincke, C. Secker, L. Schmidl, C. Geis, F. Ackermann, M. Nikolaus, C. C. Garner, H. Wardemann, G. Wolber, and H. Pruess. NMDA receptor dysfunction via unmutated human antibodies against the NR1 subunit, Ann Neurol, 85(5):771-776, 2019.
Links:
[doi:10.1002/ana.25460]
[show BibTeX]
[show abstract]
x
@article{RN266,
author = {Wenke, Nina Kerstin and Kreye, Jakob and
Andrzejak, Ewa and van Casteren, Adriana
and Leubner, Jonas and Murgueitio, Manuela
S. and Reincke, S. Momsen and Secker,
Christopher and Schmidl, Lars and Geis,
Christian and Ackermann, Frauke and
Nikolaus, Marc and Garner, Craig C. and
Wardemann, Hedda and Wolber, Gerhard and
Pruess, Harald},
title = {NMDA receptor dysfunction via unmutated
human antibodies against the NR1 subunit},
journal = {Annals of neurology},
volume = {85},
number = {5},
pages = {771-776},
abstract = {Anti‐N‐methyl‐D‐aspartate‐receptor
(NMDAR) encephalitis is the most common
autoimmune encephalitis related to
autoantibody‐mediated synaptic
dysfunction. Cerebrospinal fluid‐derived
human monoclonal NR1 autoantibodies showed
low numbers of somatic hypermutations or
were unmutated. These unexpected
germline‐configured antibodies showed
weaker binding to the NMDAR than matured
antibodies from the same patient. In
primary hippocampal neurons, germline NR1
autoantibodies strongly and specifically
reduced total and synaptic NMDAR currents
in a dose‐ and time‐dependent manner.
The findings suggest that functional NMDAR
antibodies are part of the human naïve B
cell repertoire. Given their effects on
synaptic function, they might contribute
to a broad spectrum of neuropsychiatric
symptoms.},
ISSN = {0364-5134},
DOI = {10.1002/ana.25460},
url = {http://europepmc.org/abstract/MED/30843274
https://doi.org/10.1002/ana.25460
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593665/pdf/ANA-85-771.pdf},
year = {2019},
type = {Journal Article}
}
x
NMDA receptor dysfunction via unmutated human antibodies against the NR1 subunit
Anti‐N‐methyl‐D‐aspartate‐receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid‐derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline‐configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose‐ and time‐dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms.
O. Zierau, A. Kolodziejczyk, G. Vollmer, D. Machalz, G. Wolber, D. Thieme, and A. M. Keiler. Comparison of the three SARMs RAD-140, GLPG0492 and GSK-2881078 in two different in vitro bioassays, and in an in silico androgen receptor binding assay, J Steroid Biochem, 189:81-86, 2019.
Links:
[doi:10.1016/j.jsbmb.2019.02.014]
[show BibTeX]
[show abstract]
x
@article{RN265,
author = {Zierau, Oliver and Kolodziejczyk, Annika
and Vollmer, Günter and Machalz, David
and Wolber, Gerhard and Thieme, Detlef and
Keiler, Annekathrin Martina},
title = {Comparison of the three SARMs RAD-140,
GLPG0492 and GSK-2881078 in two different
in vitro bioassays, and in an in silico
androgen receptor binding assay},
journal = {Journal of Steroid Biochemistry and
Molecular Biology},
volume = {189},
pages = {81-86},
abstract = {Selective androgen receptor modulators
comprise compounds that bind as ligands to
the androgen receptor and possess
tissue-selective activities. Ideally, they
show agonistic properties in anabolic
target tissues, while inducing
antagonistic or only weak agonistic
effects in reproductive organs. Due to
their myoanabolic effects, selective
androgen receptor modulators are included
in the list of prohibited substances and
methods of the World Anti-Doping Agency.
In the current investigation, the
androgenic potential of RAD-140,
GSK-2881078 and GLPG0492 was comparably
investigated in two different in vitro
bioassays. In the yeast androgen screen,
the androgenic effects were lower than in
the reporter gene assay in prostate
carcinoma cells (e.g. for GSK-2881078, the
EC50 values were 4.44 × 10−6M in
the yeast screen and 3.99 × 10-9M in
the prostate cells respectively). For
future investigations, it is of importance
whether the yeast androgen screen, which
has been proven to detect androgenic
compounds in urine, can detect an abuse of
the selective androgen receptor
modulators. Molecular modeling of the
binding to the androgen receptor ligand
binding domain suggests slight differences
in the binding modes of RAD-140,
GSK-2881078 and GLPG0492. In conclusion,
androgenic activity of the three
non-steroidal compounds in the two
different in vitro test systems confirmed
the results of the in silico modeling of
the androgen receptor binding.},
keywords = {Selective androgen receptor modulators
Yeast androgen screen PC3(AR)cells
Molecular modeling},
ISSN = {0960-0760},
DOI = {10.1016/j.jsbmb.2019.02.014},
url = {http://www.sciencedirect.com/science/article/pii/S0960076018306885
https://pdf.sciencedirectassets.com/271264/1-s2.0-S0960076019X00047/1-s2.0-S0960076018306885/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJr%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBmGoQIBcjjZ5EaOK3PJ%2FGurZx%2F3iAg7AxgzJBGlS1pLAiEAqq3PoXrNmhK0J8VvhGKQxD8CDm2MMxpACdgEvvCDCF0q2gMIQhACGgwwNTkwMDM1NDY4NjUiDB%2FjPXYQeqnKPMIAZSq3Axc0m%2BRD9Wt3prnTKye3Cqvo0AREbqzZ946GaterseGXxpe%2BUb3tyOJVBoXAsvayOEvYdT75FjY53skFYyeai6OYOXjZRWTEelsGyFCQf8cT3DEzx4Q%2FSuFEL5blDoqhss6bszDRC5%2FuVVpSzUmF7%2BFyAgGxxPdatNCbBmiutHGyRMn4PicJgX1DP70wJovm2MIIfOQjtVBAoW1FPcQfo4A0fJI5ShSReUYAnaXr04R8cTE%2BTTnwOVhgNPw19doX3%2FZOAC3wHvx2xdw427PkU7STXll%2FivSFUP2UPMpj5wiro1CxQicswmv0RAWfVQV%2BoN9oIuCE4eWm%2FoT86KudK0SbLCkH8hiO85Gkxien8zQf3J%2BA2aXelkRNwjG55dMxfLKxuLd5mhDnokYj7cOpwsS9sVe2WOpNw0L83GU%2FpuvVJI9vZFARLk225K%2FQ4b1pFcwGOKOAZBiAQZJ9D7JWTWR0gA8Y9KTN%2FrSCDcM7e3OCrDWcifFbCTor1FSCUFanT4fycawD7p8nphvKBxLQcZTmUo0CLG0aAL6hXvuI45m7qu0ijPUXIyCJTvyurXi9RPRuVGihaxkw98KO6wU6tAGChddaHRM2ELzStD4I3%2BltvO8qU5OvXkFpFPXsJT4YQCQafydsDiutI4rsZ8MyFKk2VmqAYvFy3yg9tm4P88k25cm8YxrYD9FZBt34b46IAXloCTW%2BjWdZAQpgxFCuBBURFwPqw%2Bz5EL4gHYjp%2BQW%2FHnmtR8SfofKETRV74Znvs9OncFyjtB09l8I8dyXKRPvZSo%2BtyGyKRjRStMbqfOcty%2BjSd%2FWSyeoJFlE6ZwZclpM4vEI%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090959Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYQ4T4FY7Z%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=eeebe89dc7b803edab1802d7f7937d0988afcf62b96a832e6f62ad813ee4b3c7&hash=80147c3643733f04f0be90d02fa9badc86eacb637119a9c2ccefcd8a0217a49c&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960076018306885&tid=spdf-742e1312-8b0a-4fb1-a7fe-20eb2f8b370f&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2019},
type = {Journal Article}
}
x
Comparison of the three SARMs RAD-140, GLPG0492 and GSK-2881078 in two different in vitro bioassays, and in an in silico androgen receptor binding assay
Selective androgen receptor modulators comprise compounds that bind as ligands to the androgen receptor and possess tissue-selective activities. Ideally, they show agonistic properties in anabolic target tissues, while inducing antagonistic or only weak agonistic effects in reproductive organs. Due to their myoanabolic effects, selective androgen receptor modulators are included in the list of prohibited substances and methods of the World Anti-Doping Agency. In the current investigation, the androgenic potential of RAD-140, GSK-2881078 and GLPG0492 was comparably investigated in two different in vitro bioassays. In the yeast androgen screen, the androgenic effects were lower than in the reporter gene assay in prostate carcinoma cells (e.g. for GSK-2881078, the EC50 values were 4.44 × 10−6M in the yeast screen and 3.99 × 10-9M in the prostate cells respectively). For future investigations, it is of importance whether the yeast androgen screen, which has been proven to detect androgenic compounds in urine, can detect an abuse of the selective androgen receptor modulators. Molecular modeling of the binding to the androgen receptor ligand binding domain suggests slight differences in the binding modes of RAD-140, GSK-2881078 and GLPG0492. In conclusion, androgenic activity of the three non-steroidal compounds in the two different in vitro test systems confirmed the results of the in silico modeling of the androgen receptor binding.
M. Grabowski, M. S. Murgueitio, M. Bermudez, J. Rademann, G. Wolber, and G. Weindl. Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening, Biochem Pharmacol, 154:148-160, 2018.
Links:
[doi:10.1016/j.bcp.2018.04.018]
[show BibTeX]
[show abstract]
x
@article{RN260,
author = {Grabowski, Maria and Murgueitio, Manuela
S. and Bermudez, Marcel and Rademann,
Jörg and Wolber, Gerhard and Weindl,
Günther},
title = {Identification of a pyrogallol derivative
as a potent and selective human TLR2
antagonist by structure-based virtual
screening},
journal = {Biochemical Pharmacology},
volume = {154},
pages = {148-160},
abstract = {Toll-like receptor 2 (TLR2) induces early
inflammatory responses to pathogen and
damage-associated molecular patterns
trough heterodimerization with either TLR1
or TLR6. Since overstimulation of TLR2
signaling is linked to several
inflammatory and metabolic diseases, TLR2
antagonists may provide therapeutic
benefits for the control of inflammatory
conditions. We present virtual screening
for the identification of novel TLR2
modulators, which combines analyses of
known ligand sets with structure-based
approaches. The 13 identified compounds
were pharmacologically characterized in
HEK293-hTLR2 cells, THP-1 macrophages and
peripheral blood mononuclear cells for
their ability to inhibit TLR2-mediated
responses. Four out of 13 selected
compounds show concentration-dependent
activity, representing a hit rate of 31%.
The most active compound is the pyrogallol
derivative MMG-11 that inhibits both
TLR2/1 and TLR2/6 signaling and shows a
higher potency than the previously
discovered CU-CPT22. Concentration ratio
analysis identified both compounds as
competitive antagonists of Pam3CSK4- and
Pam2CSK4-induced responses. Schild plot
analysis yielded apparent pA2 values of
5.73 and 6.15 (TLR2/1), and 5.80 and 6.65
(TLR2/6) for CU-CPT22 and MMG-11,
respectively. MMG-11 neither shows
cellular toxicity nor interference with
signaling induced by other TLR agonists,
IL-1β or TNF. Taken together, we
demonstrate that MMG-11 is a potent and
selective TLR2 antagonist with low
cytotoxicity rendering it a promising
pharmacological tool for the investigation
of TLR signaling and a suitable lead
structure for further chemical
optimization.},
keywords = {Drug discovery Toll-like receptors TLR2
Virtual screening Competitive antagonist
tlr},
ISSN = {0006-2952},
DOI = {10.1016/j.bcp.2018.04.018},
year = {2018},
type = {Journal Article}
}
x
Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening
Toll-like receptor 2 (TLR2) induces early inflammatory responses to pathogen and damage-associated molecular patterns trough heterodimerization with either TLR1 or TLR6. Since overstimulation of TLR2 signaling is linked to several inflammatory and metabolic diseases, TLR2 antagonists may provide therapeutic benefits for the control of inflammatory conditions. We present virtual screening for the identification of novel TLR2 modulators, which combines analyses of known ligand sets with structure-based approaches. The 13 identified compounds were pharmacologically characterized in HEK293-hTLR2 cells, THP-1 macrophages and peripheral blood mononuclear cells for their ability to inhibit TLR2-mediated responses. Four out of 13 selected compounds show concentration-dependent activity, representing a hit rate of 31%. The most active compound is the pyrogallol derivative MMG-11 that inhibits both TLR2/1 and TLR2/6 signaling and shows a higher potency than the previously discovered CU-CPT22. Concentration ratio analysis identified both compounds as competitive antagonists of Pam3CSK4- and Pam2CSK4-induced responses. Schild plot analysis yielded apparent pA2 values of 5.73 and 6.15 (TLR2/1), and 5.80 and 6.65 (TLR2/6) for CU-CPT22 and MMG-11, respectively. MMG-11 neither shows cellular toxicity nor interference with signaling induced by other TLR agonists, IL-1β or TNF. Taken together, we demonstrate that MMG-11 is a potent and selective TLR2 antagonist with low cytotoxicity rendering it a promising pharmacological tool for the investigation of TLR signaling and a suitable lead structure for further chemical optimization.
A. M. Keiler, O. Zierau, S. Wolf, P. Diel, W. Schänzer, G. Vollmer, D. Machalz, G. Wolber, and M. K. Parr. Androgen- and estrogen-receptor mediated activities of 4-hydroxytestosterone, 4-hydroxyandrostenedione and their human metabolites in yeast based assays, Toxicol Lett, 292:39-45, 2018.
Links:
[doi:10.1016/j.toxlet.2018.04.026]
[show BibTeX]
[show abstract]
x
@article{RN256,
author = {Keiler, Annekathrin Martina and Zierau,
Oliver and Wolf, Sylvi and Diel, Patrick
and Schänzer, Wilhelm and Vollmer,
Günter and Machalz, David and Wolber,
Gerhard and Parr, Maria Kristina},
title = {Androgen- and estrogen-receptor mediated
activities of 4-hydroxytestosterone,
4-hydroxyandrostenedione and their human
metabolites in yeast based assays},
journal = {Toxicology Letters},
volume = {292},
pages = {39-45},
abstract = {4-Hydroxyandrost-4-ene-3,17-dione, also
named formestane, is an irreversible
aromatase inhibitor and therapeutically
used as anti-breast cancer medication in
post-menopausal women. Currently, no
therapeutical indication led to approval
of its 17-hydroxylated analog
4-hydroxytestosterone, an anabolic
steroid. However, it is currently
investigated in a clinical trial for
breast cancer. In context with sports
doping, aromatase inhibitors are
administered to reduce estrogenic side
effects of misused anabolic substances or
their metabolites. Therefore, both
substances are prohibited in sports by the
World Anti-Doping Agency (WADA). Analysis
of urinary phase I and phase II
metabolites showed similar results for
both compounds. In the current
investigation,
4-hydroxyandrost-4-ene-3,17-dione,
4-hydroxytestosterone and seven of their
described urinary metabolites as well as
2α-hydroxyandrostenedione were tested in
the yeast androgen screen and the yeast
estrogen screen. Androgenic effects were
observed for all tested substances, except
for one, which showed anti-androgenic
properties. With regard to the yeast
estrogen screen, estrogenic effects were
observed for only two metabolites at
rather high concentrations, while six out
of the ten substances tested showed
anti-estrogenic properties. In terms of
the strong androgenic effect observed for
4-hydroxytestosterone (10−8 M),
4-hydroxyandrost-4-ene-3,17-dione
(10−8 M) and two more urinary
metabolites, the yeast androgen assay may
also be used to trace abuse in urine
samples.},
keywords = {Formestane 4-Hydroxytestosterone Doping
Molecular modeling},
ISSN = {0378-4274},
DOI = {10.1016/j.toxlet.2018.04.026},
url = {http://www.sciencedirect.com/science/article/pii/S0378427418301644
https://www.sciencedirect.com/science/article/pii/S0378427418301644?via%3Dihub},
year = {2018},
type = {Journal Article}
}
x
Androgen- and estrogen-receptor mediated activities of 4-hydroxytestosterone, 4-hydroxyandrostenedione and their human metabolites in yeast based assays
4-Hydroxyandrost-4-ene-3,17-dione, also named formestane, is an irreversible aromatase inhibitor and therapeutically used as anti-breast cancer medication in post-menopausal women. Currently, no therapeutical indication led to approval of its 17-hydroxylated analog 4-hydroxytestosterone, an anabolic steroid. However, it is currently investigated in a clinical trial for breast cancer. In context with sports doping, aromatase inhibitors are administered to reduce estrogenic side effects of misused anabolic substances or their metabolites. Therefore, both substances are prohibited in sports by the World Anti-Doping Agency (WADA). Analysis of urinary phase I and phase II metabolites showed similar results for both compounds. In the current investigation, 4-hydroxyandrost-4-ene-3,17-dione, 4-hydroxytestosterone and seven of their described urinary metabolites as well as 2α-hydroxyandrostenedione were tested in the yeast androgen screen and the yeast estrogen screen. Androgenic effects were observed for all tested substances, except for one, which showed anti-androgenic properties. With regard to the yeast estrogen screen, estrogenic effects were observed for only two metabolites at rather high concentrations, while six out of the ten substances tested showed anti-estrogenic properties. In terms of the strong androgenic effect observed for 4-hydroxytestosterone (10−8 M), 4-hydroxyandrost-4-ene-3,17-dione (10−8 M) and two more urinary metabolites, the yeast androgen assay may also be used to trace abuse in urine samples.
J. Liu, L. Chen, J. F. Joseph, A. Naß, A. Stoll, X. de la Torre, F. Botrè, G. Wolber, M. K. Parr, and M. Bureik. Combined chemical and biotechnological production of 20βOH-NorDHCMT, a long-term metabolite of Oral-Turinabol (DHCMT), J Inorg Biochem, 183:165-171, 2018.
Links:
[doi:10.1016/j.jinorgbio.2018.02.020]
[show BibTeX]
[show abstract]
x
@article{RN257,
author = {Liu, Jiaxin and Chen, Lei and Joseph, Jan
Felix and Naß, Alexandra and Stoll, Anna
and de la Torre, Xavier and Botrè,
Francesco and Wolber, Gerhard and Parr,
Maria Kristina and Bureik, Matthias},
title = {Combined chemical and biotechnological
production of 20βOH-NorDHCMT, a long-term
metabolite of Oral-Turinabol (DHCMT)},
journal = {Journal of Inorganic Biochemistry},
volume = {183},
pages = {165-171},
abstract = {Anabolic androgenic steroids (AAS) are
misused very frequently in sport
competitions as performance enhancing
agents. One of the doping compounds that
has been detected with increased frequency
in the last few years is
dehydrochloromethyltestosterone (DHCMT,
4-chloro-17β-hydroxy-17α-methylandrosta-1,4-dien-3-one;
brand name Oral Turinabol). The long-term
DHCMT metabolite 20βOH-NorDHCMT
(4-chloro-17β-hydroxymethyl-17α-methyl-18-norandrosta-1,4,13-trien-3-one)
was reported earlier to be detectable in
urine samples for more than 22 days
after DHCMT administration; however,
purified reference material was not
available so far. In this study we
demonstrate a successful combination of
Wagner-Meerwein rearrangement of DHCMT to
NorDHCMT
(4-chloro-17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one)
and subsequent whole-cell
biotransformation with a recombinant
fission yeast strain expressing the human
cytochrome P450 enzyme (CYP or P450)
CYP21A2 for the synthesis of mg amounts of
this metabolite. It was then used as
reference for the analysis of a post
administration urine of DHCMT. The
availability of this reference compound
will provide an incontestable proof for
DHCMT abuse.},
keywords = {Anabolic androgenic steroids Doping
Fission yeast Whole-cell
biotransformation},
ISSN = {0162-0134},
DOI = {10.1016/j.jinorgbio.2018.02.020},
url = {http://www.sciencedirect.com/science/article/pii/S0162013417308516
https://pdf.sciencedirectassets.com/271941/1-s2.0-S0162013418X0004X/1-s2.0-S0162013417308516/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJGMEQCIBSuXR284U5c9bmAJSN5zVw47n5M5VTNwrBmGQ8hLXVcAiAWIgoCDAYq%2BrLMnoeOj0gcwMsJ%2BK2%2F2vx37jlwfG9V%2FiraAwhBEAIaDDA1OTAwMzU0Njg2NSIMjEBFMn9jIE9t1XN2KrcDLe7GRG%2FXcw3WEgKV9YXbSGYcHYB2z7r%2B9eRerOT0zpE0wRSFgQ%2FOH9BXlp37MIlzoDaMcVajFKZS8gcJXSICZZRdMHztkVCBW4DNZa%2BJxOwJ1E6Q6vzyyBGsc%2FRoV6Xba79A94ndoN8bYy6WNuplWyrl3mWsK2vv7sI6kqAQYvwZAuSo66P%2FLefOdgACsLXUvDUtMMpSN8TmoE6MAFh%2Fj9u1tN2PHd7Si9U0lR%2BPybWjyQIZhRLaPFiPA459dq%2F0DJYDW6PUXjnBlCqj2pjkDd8G%2FcrPGVCvjIs1dEukqNYRPh9wSQFFAb5Fi0wZV3zG%2F46Hc%2FeUQIprBOrsYtxFvQ1UWxSkaVfuuRD2NfJJC%2FoyWTyuxNmD0bdhukh9A21%2B1W83wJfu%2FecDVcxhN9MqXTDLroqrvl%2BRxWFnb%2BWbs%2B%2FV9bgL2cBI6AFt4X60UAEM%2FPSuYh%2FCMbaK1dtKiQLD4N%2F7kxQrpF%2BWzb6z4YOF5hW%2F4Jm%2BgH%2B0v9v9lego%2FcMGf98VdcRdShnMV0057mzmxPdKDL4AivAyKRRfnHrHbLoO1SdPlc41DKXR%2BjK0GtocjZ5j4aUAxDDnpo7rBTq1AThXMgqWLXhCysjiDb69KUDsmtirRuTrXpezLGPDfxkFp5ofIqWUR9J0yQNBLS%2BqlghqmfiGup4DJm90ED%2Bjr269Tuc2Ri4J0zfr7%2BcI1xixL%2Fy0rAQI30TJNbf1CsDGxfVixVDBG1Fkwa3KlpjjfAGAuGKaiPkPOMJuLo8YTbs28PVbbZSstkpcNX0npq661wJ6SM3c0BNDLzt2HCCzsKCoWT8MzDtnFnmY8Er2Z7ayg87lxx0%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090907Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYZNRZYJFV%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=b720f3d2263dac5174d9f180a9eb5e614b3e41a49d79c0654e5cf2db83daf8ac&hash=b75427625e4bad8f5793e591fc5f3d24775b20f57d1f3e4528dd1440c335f22e&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0162013417308516&tid=spdf-730e9d0a-0d56-4e6a-a6a4-f7f6e8e867cf&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2018},
type = {Journal Article}
}
x
Combined chemical and biotechnological production of 20βOH-NorDHCMT, a long-term metabolite of Oral-Turinabol (DHCMT)
Anabolic androgenic steroids (AAS) are misused very frequently in sport competitions as performance enhancing agents. One of the doping compounds that has been detected with increased frequency in the last few years is dehydrochloromethyltestosterone (DHCMT, 4-chloro-17β-hydroxy-17α-methylandrosta-1,4-dien-3-one; brand name Oral Turinabol). The long-term DHCMT metabolite 20βOH-NorDHCMT (4-chloro-17β-hydroxymethyl-17α-methyl-18-norandrosta-1,4,13-trien-3-one) was reported earlier to be detectable in urine samples for more than 22 days after DHCMT administration; however, purified reference material was not available so far. In this study we demonstrate a successful combination of Wagner-Meerwein rearrangement of DHCMT to NorDHCMT (4-chloro-17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one) and subsequent whole-cell biotransformation with a recombinant fission yeast strain expressing the human cytochrome P450 enzyme (CYP or P450) CYP21A2 for the synthesis of mg amounts of this metabolite. It was then used as reference for the analysis of a post administration urine of DHCMT. The availability of this reference compound will provide an incontestable proof for DHCMT abuse.
R. Maccari, A. Del Corso, P. Paoli, I. Adornato, G. Lori, F. Balestri, M. Cappiello, A. Naß, G. Wolber, and R. Ottana. An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications, Bioorg Med Chem Lett, 28(23-24):3712-3720, 2018.
Links:
[doi:10.1016/j.bmcl.2018.10.024]
[show BibTeX]
[show abstract]
x
@article{RN261,
author = {Maccari, Rosanna and Del Corso, Antonella
and Paoli, Paolo and Adornato, Ilenia and
Lori, Giulia and Balestri, Francesco and
Cappiello, Mario and Naß, Alexandra and
Wolber, Gerhard and Ottana, Rosaria},
title = {An investigation on 4-thiazolidinone
derivatives as dual inhibitors of aldose
reductase and protein tyrosine phosphatase
1B, in the search for potential agents for
the treatment of type 2 diabetes mellitus
and its complications},
journal = {Bioorganic & Medicinal Chemistry
Letters},
volume = {28},
number = {23-24},
pages = {3712-3720},
note = {Maccari, Rosanna Del Corso, Antonella
Paoli, Paolo Adornato, Ilenia Lori, Giulia
Balestri, Francesco Cappiello, Mario Nass,
Alexandra Wolber, Gerhard Ottana, Rosaria
eng Research Support, Non-U.S. Gov't
England Bioorg Med Chem Lett. 2018 Dec
15;28(23-24):3712-3720. doi:
10.1016/j.bmcl.2018.10.024. Epub 2018 Oct
15.},
abstract = {Designed multiple ligands (DMLs),
developed to modulate simultaneously a
number of selected targets involved in
etiopathogenetic mechanisms of a
multifactorial disease, such as diabetes
mellitus (DM), are considered a promising
alternative to combinations of drugs, when
monotherapy results to be unsatisfactory.
In this work, compounds 1–17 were
synthesized and in vitro evaluated as DMLs
directed to aldose reductase (AR) and
protein tyrosine phosphatase 1B (PTP1B),
two key enzymes involved in different
events which are critical for the onset
and progression of type 2 DM and related
pathologies. Out of the tested
4-thiazolidinone derivatives, compounds 12
and 16, which exhibited potent AR
inhibitory effects along with interesting
inhibition of PTP1B, can be assumed as
lead compounds to further optimize and
balance the dual inhibitory profile.
Moreover, several structural portions were
identified as features that could be
useful to achieve simultaneous inhibition
of both human AR and PTP1B through binding
to non-catalytic regions of both target
enzymes.},
keywords = {Diabetes mellitus Designed multiple
ligands 4-Thiazolidinone derivatives
Aldose reductase Protein tyrosine
phosphatase 1B},
ISSN = {0960-894X},
DOI = {10.1016/j.bmcl.2018.10.024},
url = {http://www.sciencedirect.com/science/article/pii/S0960894X18308254
https://pdf.sciencedirectassets.com/271398/1-s2.0-S0960894X18X00225/1-s2.0-S0960894X18308254/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBfvzJJhZ1Mm5mwy0J3B5VMuELdFjoz7sIRqN8wYSzx3AiEA5SeL7MgEjFO0B9r5FrlpUN4T0hArwMRoS5vGU9JFDzkq2gMIQhACGgwwNTkwMDM1NDY4NjUiDBOT17U1MUqycs1%2FKCq3AxGHFD6W1QLBSzH%2FhBU3v8JJteKuM%2BMlhBDgx9HJr06UFb8BZd%2BHmmbs1ur5t%2FlqtRCT5APQ%2Fzl6M%2FIM8%2F6YwmMYXt9Jyw268%2FtZeBsyIAjhb9UY49j0c7v6aVzNad%2FGYTpVso5RHp%2FRIuM5L67h7pTwnakyTSI6BnpaJqI2B9kWP4JEsZprxWxTmvQw9wKd%2BZ%2Fa4mZjyJSBse7DFly8%2FGnCKXIXFbkL7gEHIAamV19AyDb7zMu0NjKSYkVhnMKdyKtcoydss0kNGXNm7HiEVwqeBYZLCKy4Gr96z9kBNqkcZ%2BCvqAOmMj10aPUlpkLbmx197FcTVJ8VImn9RLlCJRDmDXNX5yS0%2B73PI%2BEazQ5%2BwF1N29hqIzLnT1Cc5utmeZ0G5AMefCBRfmgg6E2TbmfR7Ww0V5jCzNNuAslQXXlpfPN3WJ9keKLw21X%2BSCqBPm%2Fu6Xis2DUor4OC8wohPM2ZjGByx3Gqx2LFJIPCZN3cJyL1gxaivo%2BET3s3jVm6OY0z8nVa20tLJ7Fw2PK6UzrCG3VQ%2F1Wx6deq5BIg0CjfaQgBifcwYqv%2F%2F9ZMxV6ugcNNvcoHxYgw6rmO6wU6tAGkBGWe9a6585563qyrPRyFqAu%2FM2418LDCloFTRDRH9weZ%2BgHQW1B1m%2F%2FVbRWsTdBwvnU%2BOX7Dk7jsNsnZIzAffqBskxE32pvB9%2BEG%2Fi%2F0HR72BRBiQS0zSE42%2F3v4dfwbryhRJ%2FbSj6%2BtUzOYJwiXE%2BTFI6%2Bw6by7InD6OwR0E1IdegTjGtbvA15LPpug9CTJY%2FTVHEISFL2jcir2FrGkZbfPHhgSZLoAg3rn1UL%2Buq%2FcLM4%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090911Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYRDRFHOHF%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=feaf53b1f39ea803adab835418ba489cae4c6b949016e91c0fc74405f2220c83&hash=ec623c4bd4a7063e8d68152bb19a69be7b6f0203d7e5e52fe53b81ddea1e14ee&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960894X18308254&tid=spdf-441f1cff-7ad6-4594-91a9-39f8bcc7b983&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2018},
type = {Journal Article}
}
x
An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications
Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1–17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.
R. Maccari, R. Ettari, I. Adornato, A. Naß, G. Wolber, A. Bitto, F. Mannino, F. Aliquo, G. Bruno, F. Nicolo, S. Previti, S. Grasso, M. Zappala, and R. Ottana. Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors, Bioorg Med Chem Lett, 28(3):278-283, 2018.
Links:
[doi:10.1016/j.bmcl.2017.12.053]
[show BibTeX]
[show abstract]
x
@article{RN251,
author = {Maccari, Rosanna and Ettari, Roberta and
Adornato, Ilenia and Naß, Alexandra and
Wolber, Gerhard and Bitto, Alessandra and
Mannino, Federica and Aliquo, Federica and
Bruno, Giuseppe and Nicolo, Francesco and
Previti, Santo and Grasso, Silvana and
Zappala, Maria and Ottana, Rosaria},
title = {Identification of
2-thioxoimidazolidin-4-one derivatives as
novel noncovalent proteasome and
immunoproteasome inhibitors},
journal = {Bioorganic & Medicinal Chemistry
Letters},
volume = {28},
number = {3},
pages = {278-283},
abstract = {This paper describes the design,
synthesis, and biological evaluation of
2-thioxoimidazolidin-4-one derivatives as
inhibitors of proteasome and
immunoproteasome, potential targets for
the treatment of hematological
malignancies. In particular, we focused
our efforts on the design of noncovalent
inhibitors, which might be a promising
therapeutic option potentially devoid of
drawbacks and side-effects related to
irreversible inhibition. Among all the
synthesized compounds, we identified a
panel of active inhibitors with Ki values
towards one or two chymotrypsin-like
activities of proteasome (β5c) and
immunoproteasome (β5i and β1i subunits)
in the low micromolar range. Docking
studies suggested a unique binding mode of
the molecules in the catalytic site of
immunoproteasome proteolytic subunits.},
keywords = {Proteasome Immunoproteasome
5-Arylidene-2-thioxoimidazolidin-4-ones
Non-covalent inhibitors Docking studies},
ISSN = {0960-894X},
DOI = {10.1016/j.bmcl.2017.12.053},
url = {http://www.sciencedirect.com/science/article/pii/S0960894X17312271
https://www.sciencedirect.com/science/article/pii/S0960894X17312271?via%3Dihub
https://pdf.sciencedirectassets.com/271398/1-s2.0-S0960894X18X0002X/1-s2.0-S0960894X17312271/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQDpMFAxqO8i5cWwO8J2bidQOOPWWOgX2xYgjlCqnmYpKAIgMz6zEqJOOqjcysWG%2F%2BjDZIPEG4hPysl42TQ%2BxrkJgLgq2gMIQRACGgwwNTkwMDM1NDY4NjUiDMbVMeQJp%2BA6xuTeeiq3A5yGUmiSxbecX6zyK9C0u9d8FvveGrkPLG2bgf%2FLpoQrYo2WyvA%2BBWqUubZ%2F%2F2lzFcSTpeDFbT3qjC0N3gXJAnlrhfnB4HtdM5JkFOs7rk4T5uxWa2QB%2Bxrb0uGWp6C%2FKniuq6eBMiJ59EW8Qua9SC1HjapOsfuus9g5HoQTBdya%2B%2B93vPUyT1l6n3DvNF79aTePLdf4GzCoc3La3CqQwXZ%2Bv00XVVkSLXyHqEtn%2BKj4RqGYDx5vybmCYgNtuQnt%2F4u%2FKij1yfRzcl%2BKOheRiB2UBQBFkx%2BGRL%2BqBFLx23kYZU2PrVD4ZjQMMXyglfn7R41W1Ts944jcTs7eKtPEaIuwbGZFi3rfxU%2BBL%2BrhXsqDJMbPTE%2BrqYpk6xiwMVJaY6kJH62kCLazVZrQ49cjhJjxeJti4aqVRxjr4XOP%2FJ9EatP%2BZoD3q47yNzrS1dG3FcQOp6Rtx1LGD9QPU8GrLpoB2%2F%2BrydWuCVqCFWw5iNbyp05sWQsfmSpFEMzsvkKO%2FCw0bATpkHdkF6WOn0A1lXIOsI0cDUPAe1xWJ3L0KZySQ0UZUqXJ8Gw4v%2FTlL5BY%2FUxSnor26xYwn6aO6wU6tAHBqopuW5pcz%2FJI%2BrCyUdYGVL8ZGUcN9osxZNHlsdHl%2FPSb5Ey3HqdiHTks1pszrFK8F0ZxsQNCYajkgKT3SAzhgrTmaNYfXyzLVkl3rMbW5QA0SqgsnR79JfHgUXuHGBnWyrsVF5mu9vmFjpTB4j2VqmtMOIjghMdHO%2FOIcR59ey2VTJQKE1Ulq0WJqECO72nl8nHMFEUoBLcWlCu5cwJlo5NxAcL7qC1hNPBzJlNFYMqU07s%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090916Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY5J43SP76%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=e7c2580b1bb9072e94b21c17a17e77638c77cc9426365c1d5789e72f4ef95b81&hash=61d4515aaf52ead90206956d3b9b1b4f62c4062ab11c5f1b52d8f8dd8b4e4eb5&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960894X17312271&tid=spdf-2602928c-1628-4f42-ac59-ecd3a11225cf&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2018},
type = {Journal Article}
}
x
Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors
This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with Ki values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.
D. Schaller, M. G. Gündüz, F. X. Zhang, G. W. Zamponi, and G. Wolber. Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity, Eur J Med Chem, 155:1-12, 2018.
Links:
[doi:10.1016/j.ejmech.2018.05.032]
[show BibTeX]
[show abstract]
x
@article{RN258,
author = {Schaller, David and Gündüz, Miyase
Gözde and Zhang, Fang Xiong and Zamponi,
Gerald W. and Wolber, Gerhard},
title = {Binding mechanism investigations guiding
the synthesis of novel condensed
1,4-dihydropyridine derivatives with
L-/T-type calcium channel blocking
activity},
journal = {European Journal of Medicinal Chemistry},
volume = {155},
pages = {1-12},
abstract = {Nifedipine and isradipine are prominent
examples of calcium channel blockers with
a 1,4-dihydropyridine (DHP) scaffold.
Although successfully used in clinics
since decades for the treatment of
hypertension, the binding mechanism to
their target, the L-type voltage-gated
calcium channel Cav1.2, is still
incompletely understood. Recently, novel
DHP derivatives with a condensed ring
system have been discovered that show
distinct selectivity profiles to different
calcium channel subtypes. This property
renders this DHP class as a promising tool
to achieve selectivity towards distinct
calcium channel subtypes. In this study,
we identified a common binding mode for
prominent DHPs nifedipine and isradipine
using docking and pharmacophore analysis
that is also able to explain the
structure-activity relationship of a small
subseries of DHP derivatives with a
condensed ring system. These findings were
used to guide the synthesis of twenty-two
novel DHPs. An extensive characterization
using 1H NMR, 13C NMR, mass spectra and
elemental analysis was followed by whole
cell patch clamp assays for analyzing
activity at Cav1.2 and Cav3.2. Two
compounds were identified with significant
activity against Cav1.2. Additionally, we
identified four compounds active against
Cav3.2 of which three were selective over
Cav1.2. Novel binding modes were analyzed
using docking and pharmacophore analysis
as well as molecular dynamics
simulations.},
keywords = {1,4-dihydropyridine Hexahydroquinoline
Calcium channel Whole cell patch clamp
Binding mechanism Molecular modelling},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2018.05.032},
url = {https://www.sciencedirect.com/science/article/pii/S0223523418304458
https://pdf.sciencedirectassets.com/271932/1-s2.0-S0223523418X00129/1-s2.0-S0223523418304458/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQDpMFAxqO8i5cWwO8J2bidQOOPWWOgX2xYgjlCqnmYpKAIgMz6zEqJOOqjcysWG%2F%2BjDZIPEG4hPysl42TQ%2BxrkJgLgq2gMIQRACGgwwNTkwMDM1NDY4NjUiDMbVMeQJp%2BA6xuTeeiq3A5yGUmiSxbecX6zyK9C0u9d8FvveGrkPLG2bgf%2FLpoQrYo2WyvA%2BBWqUubZ%2F%2F2lzFcSTpeDFbT3qjC0N3gXJAnlrhfnB4HtdM5JkFOs7rk4T5uxWa2QB%2Bxrb0uGWp6C%2FKniuq6eBMiJ59EW8Qua9SC1HjapOsfuus9g5HoQTBdya%2B%2B93vPUyT1l6n3DvNF79aTePLdf4GzCoc3La3CqQwXZ%2Bv00XVVkSLXyHqEtn%2BKj4RqGYDx5vybmCYgNtuQnt%2F4u%2FKij1yfRzcl%2BKOheRiB2UBQBFkx%2BGRL%2BqBFLx23kYZU2PrVD4ZjQMMXyglfn7R41W1Ts944jcTs7eKtPEaIuwbGZFi3rfxU%2BBL%2BrhXsqDJMbPTE%2BrqYpk6xiwMVJaY6kJH62kCLazVZrQ49cjhJjxeJti4aqVRxjr4XOP%2FJ9EatP%2BZoD3q47yNzrS1dG3FcQOp6Rtx1LGD9QPU8GrLpoB2%2F%2BrydWuCVqCFWw5iNbyp05sWQsfmSpFEMzsvkKO%2FCw0bATpkHdkF6WOn0A1lXIOsI0cDUPAe1xWJ3L0KZySQ0UZUqXJ8Gw4v%2FTlL5BY%2FUxSnor26xYwn6aO6wU6tAHBqopuW5pcz%2FJI%2BrCyUdYGVL8ZGUcN9osxZNHlsdHl%2FPSb5Ey3HqdiHTks1pszrFK8F0ZxsQNCYajkgKT3SAzhgrTmaNYfXyzLVkl3rMbW5QA0SqgsnR79JfHgUXuHGBnWyrsVF5mu9vmFjpTB4j2VqmtMOIjghMdHO%2FOIcR59ey2VTJQKE1Ulq0WJqECO72nl8nHMFEUoBLcWlCu5cwJlo5NxAcL7qC1hNPBzJlNFYMqU07s%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090934Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY5J43SP76%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=c849855703227baf4068983f2ec0fd8823703c021692f5938ab30d1eb2fa9bff&hash=2b4e25a1b06c86632253879a8372204f4f5ae2a04e12ae7231cd5b4a48705142&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0223523418304458&tid=spdf-307057ac-8507-41f8-9a2e-60eca516f2bb&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2018},
type = {Journal Article}
}
x
Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity
Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes. In this study, we identified a common binding mode for prominent DHPs nifedipine and isradipine using docking and pharmacophore analysis that is also able to explain the structure-activity relationship of a small subseries of DHP derivatives with a condensed ring system. These findings were used to guide the synthesis of twenty-two novel DHPs. An extensive characterization using 1H NMR, 13C NMR, mass spectra and elemental analysis was followed by whole cell patch clamp assays for analyzing activity at Cav1.2 and Cav3.2. Two compounds were identified with significant activity against Cav1.2. Additionally, we identified four compounds active against Cav3.2 of which three were selective over Cav1.2. Novel binding modes were analyzed using docking and pharmacophore analysis as well as molecular dynamics simulations.
R. Schulz, A. Atef, D. Becker, F. Gottschalk, C. Tauber, S. Wagner, C. Arkona, A. A. Abdel-Hafez, H. H. Farag, J. Rademann, and G. Wolber. Phenylthiomethyl ketone-based fragments show selective and irreversible inhibition of enteroviral 3C proteases, J Med Chem, 61(3):1218-1230, 2018.
Links:
[doi:10.1021/acs.jmedchem.7b01440]
[show BibTeX]
[show abstract]
x
@article{RN252,
author = {Schulz, Robert and Atef, Amira and
Becker, Daniel and Gottschalk, Franziska
and Tauber, Carolin and Wagner, Stefan and
Arkona, Christoph and Abdel-Hafez, Atef A.
and Farag, Hassan H. and Rademann, Jörg
and Wolber, Gerhard},
title = {Phenylthiomethyl ketone-based fragments
show selective and irreversible inhibition
of enteroviral 3C proteases},
journal = {Journal of Medicinal Chemistry},
volume = {61},
number = {3},
pages = {1218-1230},
abstract = {Lead structure discovery mainly focuses
on the identification of noncovalently
binding ligands. Covalent linkage,
however, is an essential binding mechanism
for a multitude of successfully marketed
drugs although discovered by serendipity
in most cases. We present a concept for
the design of fragments covalently binding
to proteases. Covalent linkage enables
fragment binding unrelated to affinity to
shallow protein binding sites and at the
same time allows differentiated targeted
hit verification and binding location
verification through mass spectrometry. We
describe a systematic and rational
computational approach for the
identification of covalently binding
fragments from compound collections
inhibiting enteroviral 3C protease, a
target with high therapeutic potential. By
implementing reactive groups potentially
forming covalent bonds as chemical feature
in our 3D pharmacophore methodology,
covalent binders were discovered by
high-throughput virtual screening. We
present careful experimental validation of
the virtual hits using enzymatic assays
and mass spectrometry unraveling a novel,
previously unknown irreversible inhibition
of the 3C protease by phenylthiomethyl
ketone-based fragments. Subsequent
synthetic optimization through fragment
growing and reactivity analysis against
catalytic and non-catalytic cysteines
revealed specific irreversible 3C protease
inhibition.},
ISSN = {0022-2623},
DOI = {10.1021/acs.jmedchem.7b01440},
url = {http://dx.doi.org/10.1021/acs.jmedchem.7b01440
https://pubs.acs.org/doi/pdfplus/10.1021/acs.jmedchem.7b01440},
year = {2018},
type = {Journal Article}
}
x
Phenylthiomethyl ketone-based fragments show selective and irreversible inhibition of enteroviral 3C proteases
Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry. We describe a systematic and rational computational approach for the identification of covalently binding fragments from compound collections inhibiting enteroviral 3C protease, a target with high therapeutic potential. By implementing reactive groups potentially forming covalent bonds as chemical feature in our 3D pharmacophore methodology, covalent binders were discovered by high-throughput virtual screening. We present careful experimental validation of the virtual hits using enzymatic assays and mass spectrometry unraveling a novel, previously unknown irreversible inhibition of the 3C protease by phenylthiomethyl ketone-based fragments. Subsequent synthetic optimization through fragment growing and reactivity analysis against catalytic and non-catalytic cysteines revealed specific irreversible 3C protease inhibition.
A. Tkachenko, M. Bermudez, S. Irmer-Stooff, D. Genkinger, F. Henkler-Stephani, G. Wolber, and A. Luch. Nuclear transport of the human aryl hydrocarbon receptor and subsequent gene induction relies on its residue histidine 291, Arch Toxicol, 92(3):1151-1160, 2018.
Links:
[doi:10.1007/s00204-017-2129-0]
[show BibTeX]
[show abstract]
x
@article{RN249,
author = {Tkachenko, A. and Bermudez, M. and
Irmer-Stooff, S. and Genkinger, D. and
Henkler-Stephani, F. and Wolber, G. and
Luch, A.},
title = {Nuclear transport of the human aryl
hydrocarbon receptor and subsequent gene
induction relies on its residue histidine
291},
journal = {Archives of Toxicology},
volume = {92},
number = {3},
pages = {1151-1160},
abstract = {The aryl hydrocarbon receptor (AHR) is a
ligand-dependent transcription factor
involved in the metabolism of
physiological substances and xenobiotics,
representing an interesting target in both
toxicology and pharmacology. In this
study, we investigated the
ligand-dependent conjunction of nuclear
import of the human AHR in living cells
and target gene induction. Our findings
strengthen the theory that the AHR
triggers a precisely defined and rapid
reaction upon binding to endogenous
ligands, while the xenobiotic
β-naphthoflavone only induces rather
unspecific and slow effects. To better
illuminate the ligand-mediated responses
of the human AHR, we applied site-directed
mutagenesis and identified histidine 291
as key residue for AHR functionality,
essential for both nuclear import and
target gene induction. Contrary, replacing
histidine at position 291 by alanine did
not affect nucleo-cytoplasmic shuttling,
showing that permanent endogenous import
and ligand-induced import of the AHR into
the nucleus are two independent and
differently regulated processes. Combining
these observations with our structural
investigations using a homology model of
the AHR-PAS B domain, we suggest a dual
role of histidine 291: (1) a major role
for shaping the ligand binding site
including direct interactions with ligands
and, (2) an essential role for the
conformational dynamics of a PAS B loop,
which most likely influences the
association of the AHR with the AHR
nuclear translocator through interference
with their protein–protein interface.},
ISSN = {1432-0738},
DOI = {10.1007/s00204-017-2129-0},
url = {https://doi.org/10.1007/s00204-017-2129-0
https://link.springer.com/content/pdf/10.1007%2Fs00204-017-2129-0.pdf},
year = {2018},
type = {Journal Article}
}
x
Nuclear transport of the human aryl hydrocarbon receptor and subsequent gene induction relies on its residue histidine 291
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in the metabolism of physiological substances and xenobiotics, representing an interesting target in both toxicology and pharmacology. In this study, we investigated the ligand-dependent conjunction of nuclear import of the human AHR in living cells and target gene induction. Our findings strengthen the theory that the AHR triggers a precisely defined and rapid reaction upon binding to endogenous ligands, while the xenobiotic β-naphthoflavone only induces rather unspecific and slow effects. To better illuminate the ligand-mediated responses of the human AHR, we applied site-directed mutagenesis and identified histidine 291 as key residue for AHR functionality, essential for both nuclear import and target gene induction. Contrary, replacing histidine at position 291 by alanine did not affect nucleo-cytoplasmic shuttling, showing that permanent endogenous import and ligand-induced import of the AHR into the nucleus are two independent and differently regulated processes. Combining these observations with our structural investigations using a homology model of the AHR-PAS B domain, we suggest a dual role of histidine 291: (1) a major role for shaping the ligand binding site including direct interactions with ligands and, (2) an essential role for the conformational dynamics of a PAS B loop, which most likely influences the association of the AHR with the AHR nuclear translocator through interference with their protein–protein interface.
F. Yang, D. Machalz, S. Wang, Z. Li, G. Wolber, and M. Bureik. A common polymorphic variant of UGT1A5 displays increased activity due to optimized cofactor binding, Febs Lett, 592(11):1837-1846, 2018.
Links:
[doi:10.1002/1873-3468.13072]
[show BibTeX]
[show abstract]
x
@article{RN259,
author = {Yang, Fan and Machalz, David and Wang,
Sisi and Li, Zhengyi and Wolber, Gerhard
and Bureik, Matthias},
title = {A common polymorphic variant of UGT1A5
displays increased activity due to
optimized cofactor binding},
journal = {FEBS Letters},
volume = {592},
number = {11},
pages = {1837-1846},
abstract = {Uridine
diphosphate‐glucuronosyltransferases
(UGTs) are the most important phase II
enzymes in human drug metabolism. Using
permeabilized recombinant fission yeast
cells (enzyme bags), we demonstrate that
UGT1A5 can catalyze an N‐glucuronidation
reaction. We characterized two new
polymorphic UGT1A5 variants: a common
ninefold mutant (UGT1A5*8) with
double‐fold activity and a much rarer
sixfold mutant (UGT1A5*9), which has the
same activity as the wild‐type.
Molecular modeling studies indicate that
the minor effects of all mutations, except
for Gly259Arg, are due to their distance
to the substrate binding site. Extensive
molecular dynamics simulations revealed
that the Gly259Arg mutation stabilizes
helix Q through a newly formed hydrogen
bonding network, which places the cofactor
in a much more favorable geometry in
UGT1A5*8 as compared to the wild‐type.},
DOI = {10.1002/1873-3468.13072},
url = {https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1873-3468.13072
https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/1873-3468.13072},
year = {2018},
type = {Journal Article}
}
x
A common polymorphic variant of UGT1A5 displays increased activity due to optimized cofactor binding
Uridine diphosphate‐glucuronosyltransferases (UGTs) are the most important phase II enzymes in human drug metabolism. Using permeabilized recombinant fission yeast cells (enzyme bags), we demonstrate that UGT1A5 can catalyze an N‐glucuronidation reaction. We characterized two new polymorphic UGT1A5 variants: a common ninefold mutant (UGT1A5*8) with double‐fold activity and a much rarer sixfold mutant (UGT1A5*9), which has the same activity as the wild‐type. Molecular modeling studies indicate that the minor effects of all mutations, except for Gly259Arg, are due to their distance to the substrate binding site. Extensive molecular dynamics simulations revealed that the Gly259Arg mutation stabilizes helix Q through a newly formed hydrogen bonding network, which places the cofactor in a much more favorable geometry in UGT1A5*8 as compared to the wild‐type.
H. A. Abuelizz, R. Al-Salahi, J. Al-Asri, J. Mortier, M. Marzouk, E. Ezzeldin, A. A. Ali, M. G. Khalil, G. Wolber, H. A. Ghabbour, A. A. Almehizia, and G. A. Abdel Jaleel. Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives, Chem Cent J, 11(1):103, 2017.
Links:
[doi:10.1186/s13065-017-0321-1]
[show BibTeX]
[show abstract]
x
@article{RN207,
author = {Abuelizz, Hatem A. and Al-Salahi, Rashad
and Al-Asri, Jamil and Mortier, Jérémie
and Marzouk, Mohamed and Ezzeldin, Essam
and Ali, Azza A. and Khalil, Mona G. and
Wolber, Gerhard and Ghabbour, Hazem A. and
Almehizia, Abdulrahman A. and Abdel
Jaleel, Gehad A.},
title = {Synthesis, crystallographic
characterization, molecular docking and
biological activity of isoquinoline
derivatives},
journal = {Chemistry Central Journal},
volume = {11},
number = {1},
pages = {103},
abstract = {The main objective of this work was to
synthesize novel compounds with a
benzo[de][1,2,4]triazolo[5,1-a]isoquinoline
scaffold by employing
(dioxo-benzo[de]isoquinolin-2-yl) thiourea
as a building block. Molecular docking was
conducted in the COX-2 active site to
predict the plausible binding mode and
rationalize the structure–activity
relationship of the synthesized compounds.
The structures of the synthesized
compounds were confirmed by HREI-MS, and
NMR spectra along with X-ray diffraction
were collected for products 1 and 5.
Thereafter, anti-inflammatory effect of
molecules 1–20 was evaluated in vivo
using carrageenan-induced paw edema
method, revealing significant inhibition
potency in albino rats with an activity
comparable to that of the standard drugs
indomethacin. Compounds 8, 9, 15 and 16
showed the highest anti-inflammatory
activity. However, thermal sensitivity-hot
plat test, a radiological examination and
motor coordination assessment were
performed to test the activity against
rheumatoid arthritis. The obtained results
indicate promising anti-arthritic activity
for compounds 9 and 15 as significant
reduction of the serum level of
interleukin-1β [IL-1β], cyclooxygenase-2
[COX-2] and prostaglandin E2 [PGE2] was
observed in CFA rats.},
ISSN = {1752-153X},
DOI = {10.1186/s13065-017-0321-1},
url = {https://doi.org/10.1186/s13065-017-0321-1
https://ccj.springeropen.com/track/pdf/10.1186/s13065-017-0321-1?site= ccj.springeropen.com},
year = {2017},
type = {Journal Article}
}
x
Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives
The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scaffold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was conducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure–activity relationship of the synthesized compounds. The structures of the synthesized compounds were confirmed by HREI-MS, and NMR spectra along with X-ray diffraction were collected for products 1 and 5. Thereafter, anti-inflammatory effect of molecules 1–20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibition potency in albino rats with an activity comparable to that of the standard drugs indomethacin. Compounds 8, 9, 15 and 16 showed the highest anti-inflammatory activity. However, thermal sensitivity-hot plat test, a radiological examination and motor coordination assessment were performed to test the activity against rheumatoid arthritis. The obtained results indicate promising anti-arthritic activity for compounds 9 and 15 as significant reduction of the serum level of interleukin-1β [IL-1β], cyclooxygenase-2 [COX-2] and prostaglandin E2 [PGE2] was observed in CFA rats.
M. Bermudez, A. Bock, F. Krebs, U. Holzgrabe, K. Mohr, M. J. Lohse, and G. Wolber. Ligand-specific restriction of extracellular conformational dynamics constrains signaling of the M2 muscarinic receptor, ACS Chem Biol, 12(7):1743-1748, 2017.
Links:
[doi:10.1021/acschembio.7b00275]
[show BibTeX]
[show abstract]
x
@article{RN203,
author = {Bermudez, Marcel and Bock, Andreas and
Krebs, Fabian and Holzgrabe, Ulrike and
Mohr, Klaus and Lohse, Martin J. and
Wolber, Gerhard},
title = {Ligand-specific restriction of
extracellular conformational dynamics
constrains signaling of the M2 muscarinic
receptor},
journal = {ACS Chemical Biology},
volume = {12},
number = {7},
pages = {1743-1748},
abstract = {G protein-coupled receptors transmit
extracellular signals across cell
membranes via different G protein classes
and β-arrestins. Some pathways may be
therapeutically beneficial, whereas others
may be detrimental under certain
pathophysiological conditions. For many
GPCRs, biased agonists are available,
which preferentially signal through one
pathway or a subset of pathways, and
harnessing biased agonism could be a
potential novel therapeutic strategy.
However, the incomplete mechanistic
understanding of biased agonism hampers
rational design of biased ligands. Using
the muscarinic M2 receptor as a model
system, we have analyzed the relationship
between ligand-dependent conformational
changes as revealed in all-atom MD
simulations and the activation of specific
G proteins. We find that the extent of
closure of the extracellular, allosteric
binding site interferes with the
activation of certain G proteins. Our data
allow the rational design of Gi-biased
agonists at the M2 receptor and delineate
a simple principle which may be translated
to other GPRCs.},
keywords = {gpcr},
DOI = {10.1021/acschembio.7b00275},
url = {http://pubs.acs.org/doi/pdfplus/10.1021/acschembio.7b00275},
year = {2017},
type = {Journal Article}
}
x
Ligand-specific restriction of extracellular conformational dynamics constrains signaling of the M2 muscarinic receptor
G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and β-arrestins. Some pathways may be therapeutically beneficial, whereas others may be detrimental under certain pathophysiological conditions. For many GPCRs, biased agonists are available, which preferentially signal through one pathway or a subset of pathways, and harnessing biased agonism could be a potential novel therapeutic strategy. However, the incomplete mechanistic understanding of biased agonism hampers rational design of biased ligands. Using the muscarinic M2 receptor as a model system, we have analyzed the relationship between ligand-dependent conformational changes as revealed in all-atom MD simulations and the activation of specific G proteins. We find that the extent of closure of the extracellular, allosteric binding site interferes with the activation of certain G proteins. Our data allow the rational design of Gi-biased agonists at the M2 receptor and delineate a simple principle which may be translated to other GPRCs.
J. Mortier, J. R. C. Prévost, D. Sydow, S. Teuchert, C. Omieczynski, M. Bermudez, R. Frédérick, and G. Wolber. Arginase structure and inhibition: Catalytic site plasticity reveals new modulation possibilities, Scientific Reports, 7(1):13616, 2017.
Links:
[doi:10.1038/s41598-017-13366-4]
[show BibTeX]
[show abstract]
x
@article{RN248,
author = {Mortier, Jérémie and Prévost, Julien
R. C. and Sydow, Dominique and Teuchert,
Sabine and Omieczynski, Christian and
Bermudez, Marcel and Frédérick, Raphaël
and Wolber, Gerhard},
title = {Arginase structure and inhibition:
Catalytic site plasticity reveals new
modulation possibilities},
journal = {Scientific Reports},
volume = {7},
number = {1},
pages = {13616},
abstract = {Metalloenzyme arginase is a
therapeutically relevant target associated
with tumor growth. To fight cancer
immunosuppression, arginase activity can
be modulated by small chemical inhibitors
binding to its catalytic center. To better
understand molecular mechanisms of
arginase inhibition, a careful
computer-aided mechanistic structural
investigation of this enzyme was
conducted. Using molecular dynamics (MD)
simulations in the microsecond range, key
regions of the protein active site were
identified and their flexibility was
evaluated and compared. A cavity opening
phenomenon was observed, involving three
loops directly interacting with all known
ligands, while metal coordinating regions
remained motionless. A novel dynamic 3D
pharmacophore analysis method termed
dynophores has been developed that allows
for the construction of a single 3D-model
comprising all ligand-enzyme interactions
occurring throughout a complete MD
trajectory. This new technique for the in
silico study of intermolecular
interactions allows for loop flexibility
analysis coupled with movements and
conformational changes of bound ligands.
Presented MD studies highlight the
plasticity of the size of the arginase
active site, leading to the hypothesis
that larger ligands can enter the cavity
of arginase. Experimental testing of a
targeted fragment library substituted by
different aliphatic groups validates this
hypothesis, paving the way for the design
of arginase inhibitors with novel binding
patterns.},
keywords = {dynophore},
ISSN = {2045-2322},
DOI = {10.1038/s41598-017-13366-4},
url = {https://doi.org/10.1038/s41598-017-13366-4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648838/pdf/41598_2017_Article_13366.pdf},
year = {2017},
type = {Journal Article}
}
x
Arginase structure and inhibition: Catalytic site plasticity reveals new modulation possibilities
Metalloenzyme arginase is a therapeutically relevant target associated with tumor growth. To fight cancer immunosuppression, arginase activity can be modulated by small chemical inhibitors binding to its catalytic center. To better understand molecular mechanisms of arginase inhibition, a careful computer-aided mechanistic structural investigation of this enzyme was conducted. Using molecular dynamics (MD) simulations in the microsecond range, key regions of the protein active site were identified and their flexibility was evaluated and compared. A cavity opening phenomenon was observed, involving three loops directly interacting with all known ligands, while metal coordinating regions remained motionless. A novel dynamic 3D pharmacophore analysis method termed dynophores has been developed that allows for the construction of a single 3D-model comprising all ligand-enzyme interactions occurring throughout a complete MD trajectory. This new technique for the in silico study of intermolecular interactions allows for loop flexibility analysis coupled with movements and conformational changes of bound ligands. Presented MD studies highlight the plasticity of the size of the arginase active site, leading to the hypothesis that larger ligands can enter the cavity of arginase. Experimental testing of a targeted fragment library substituted by different aliphatic groups validates this hypothesis, paving the way for the design of arginase inhibitors with novel binding patterns.
M. S. Murgueitio, S. Ebner, P. Hörtnagl, C. Rakers, R. Bruckner, P. Henneke, G. Wolber, and S. Santos-Sierra. Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2), Biochimica et Biophysica Acta (BBA), General Subjects, 1861(11):2680-2689, 2017.
Links:
[doi:10.1016/j.bbagen.2017.07.011]
[show BibTeX]
[show abstract]
x
@article{RN205,
author = {Murgueitio, M. S. and Ebner, S. and
Hörtnagl, P. and Rakers, C. and Bruckner,
R. and Henneke, P. and Wolber, G. and
Santos-Sierra, S.},
title = {Enhanced immunostimulatory activity of in
silico discovered agonists of Toll-like
receptor 2 (TLR2)},
journal = {Biochimica et Biophysica Acta (BBA),
General Subjects},
volume = {1861},
number = {11},
pages = {2680-2689},
abstract = {Emergent therapies in anticancer
vaccination use Toll-like receptors (TLRs)
agonists as dendritic cell (DC) vaccine
adjuvants. DCs from the patient are
isolated, stimulated with TLR agonists and
tumor antigens ex vivo and then infused
back into the patient. Although some TLR
ligands have been tested in clinical
trials, novel TLR agonists with improved
immunomodulatory properties are essential
to optimize treatment success. We report
on the discovery of small-molecule TLR2
agonists, with favorable properties as
synthetic adjuvants. We performed a shape-
and featured-based similarity virtual
screening against a commercially available
compound library. The selected virtual
hits were experimentally tested in
TLR2-reporter cells and their activity in
phagocytes and DCs was characterized. A
binding model of the compounds to TLR2
(docking studies) was proposed. Through a
virtual screening approach against a
library of three million compounds four
virtual hits (AG1, AG2, AG3, AG4) were
found to synergistically augment the NF-kB
activation induced by the lipopeptide
ligand Pam3CSK4 in luciferase reporter
assays using HEK293-TLR2 cells. Biacore
experiments indicated that AG1–AG4 are
ago-allosteric modulators of TLR2 and AG2
bound TLR2 with high affinity (KD 0.8μM).
The compounds induced TNF-α production in
human peripheral blood mononuclear cells
(PBMCs) and they activated DCs as
indicated by IL-12 production and
upregulation of CD83/CD86. Following a
combined in silico/in vitro approach we
have discovered TLR2-agonists (AG1–AG4)
that activate human and mouse immune
cells. We introduce four novel TLR2
ago-allosteric modulators that stimulate
myeloid cell activity and constitute
promising candidates as synthetic
adjuvants.},
keywords = {Toll-like receptor Cancer vaccination
Virtual screening Adjuvants Dendritic cell
Inflammation},
ISSN = {0304-4165},
DOI = {10.1016/j.bbagen.2017.07.011},
url = {http://www.sciencedirect.com/science/article/pii/S0304416517302222
https://ac.els-cdn.com/S0304416517302222/1-s2.0-S0304416517302222-main.pdf?_tid= 0e5b1604-ba65-11e7-9947-00000aab0f27&acdnat=1509033065_be28cc321c81e00bd2ec48eb34559e40},
year = {2017},
type = {Journal Article}
}
x
Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2)
Emergent therapies in anticancer vaccination use Toll-like receptors (TLRs) agonists as dendritic cell (DC) vaccine adjuvants. DCs from the patient are isolated, stimulated with TLR agonists and tumor antigens ex vivo and then infused back into the patient. Although some TLR ligands have been tested in clinical trials, novel TLR agonists with improved immunomodulatory properties are essential to optimize treatment success. We report on the discovery of small-molecule TLR2 agonists, with favorable properties as synthetic adjuvants. We performed a shape- and featured-based similarity virtual screening against a commercially available compound library. The selected virtual hits were experimentally tested in TLR2-reporter cells and their activity in phagocytes and DCs was characterized. A binding model of the compounds to TLR2 (docking studies) was proposed. Through a virtual screening approach against a library of three million compounds four virtual hits (AG1, AG2, AG3, AG4) were found to synergistically augment the NF-kB activation induced by the lipopeptide ligand Pam3CSK4 in luciferase reporter assays using HEK293-TLR2 cells. Biacore experiments indicated that AG1–AG4 are ago-allosteric modulators of TLR2 and AG2 bound TLR2 with high affinity (KD 0.8μM). The compounds induced TNF-α production in human peripheral blood mononuclear cells (PBMCs) and they activated DCs as indicated by IL-12 production and upregulation of CD83/CD86. Following a combined in silico/in vitro approach we have discovered TLR2-agonists (AG1–AG4) that activate human and mouse immune cells. We introduce four novel TLR2 ago-allosteric modulators that stimulate myeloid cell activity and constitute promising candidates as synthetic adjuvants.
M. S. Murgueitio, C. Rakers, A. Frank, and G. Wolber. Balancing Inflammation: Computational Design of Small-Molecule Toll-like Receptor Modulators, Trends Pharmacol Sci, 38(2):155-168, 2017.
Links:
[doi:10.1016/j.tips.2016.10.007]
[show BibTeX]
[show abstract]
x
@article{RN201,
author = {Murgueitio, Manuela S. and Rakers,
Christin and Frank, Anne and Wolber,
Gerhard},
title = {Balancing Inflammation: Computational
Design of Small-Molecule Toll-like
Receptor Modulators},
journal = {Trends in Pharmacological Sciences},
volume = {38},
number = {2},
pages = {155-168},
abstract = {As essential proteins of the innate
immune system, Toll-like receptors (TLRs)
are involved in a plethora of
physiological pathologies and their
modulation is an ongoing quest in the
field of drug discovery. Although TLRs
recognize an unusually broad range of
different molecular patterns, only a few
small-molecule TLR modulators have been
reported to date. Recent advances in
crystallography and in silico techniques
provide promising opportunities for TLR
investigations and drug design. Here,
three application areas for computational
approaches are considered: (i) exploration
of TLR structure and activation; (ii)
understanding TLR modulation; and (iii)
TLR drug discovery. By providing an
overview on state-of-the-art computational
methods, we highlight the value of
molecular modeling in mechanistically
understanding TLR function and guiding
drug design.},
ISSN = {0165-6147},
DOI = {10.1016/j.tips.2016.10.007},
url = {http://dx.doi.org/10.1016/j.tips.2016.10.007
http://ac.els-cdn.com/S0165614716301377/1-s2.0-S0165614716301377-main.pdf?_tid= 8ea85ae0-b7c0-11e6-8b76-00000aab0f27&acdnat=1480595013_5bb0b3aaeb0d4f16e65dd6468b9b7091},
year = {2017},
type = {Journal Article}
}
x
Balancing Inflammation: Computational Design of Small-Molecule Toll-like Receptor Modulators
As essential proteins of the innate immune system, Toll-like receptors (TLRs) are involved in a plethora of physiological pathologies and their modulation is an ongoing quest in the field of drug discovery. Although TLRs recognize an unusually broad range of different molecular patterns, only a few small-molecule TLR modulators have been reported to date. Recent advances in crystallography and in silico techniques provide promising opportunities for TLR investigations and drug design. Here, three application areas for computational approaches are considered: (i) exploration of TLR structure and activation; (ii) understanding TLR modulation; and (iii) TLR drug discovery. By providing an overview on state-of-the-art computational methods, we highlight the value of molecular modeling in mechanistically understanding TLR function and guiding drug design.
R. Ottana, P. Paoli, A. Naß, G. Lori, V. Cardile, I. Adornato, A. Rotondo, A. C. Eleonora Graziano, G. Wolber, and R. Maccari. Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents, Eur J Med Chem, 127:840-858, 2017.
Links:
[doi:10.1016/j.ejmech.2016.10.063]
[show BibTeX]
[show abstract]
x
@article{RN199,
author = {Ottana, Rosaria and Paoli, Paolo and
Naß, Alexandra and Lori, Giulia and
Cardile, Venera and Adornato, Ilenia and
Rotondo, Archimede and Eleonora Graziano,
Adriana Carol and Wolber, Gerhard and
Maccari, Rosanna},
title = {Discovery of
4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic
acid derivatives active as novel potent
allosteric inhibitors of protein tyrosine
phosphatase 1B: In silico studies and in
vitro evaluation as insulinomimetic and
anti-inflammatory agents},
journal = {European Journal of Medicinal Chemistry},
volume = {127},
pages = {840-858},
abstract = {New
4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic
acids (5) and 2-thioxo-4-thiazolidinone
analogues (6) were synthesised as a part
of a continuing search for new inhibitors
of protein tyrosine phosphatase 1B
(PTP1B), an enzyme which is implicated in
metabolic disorders and inflammatory
signaling. Most of the tested compounds
were shown to be potent PTP1B inhibitors.
Moreover, their inhibition mechanism was
markedly influenced by the substituents in
the positions 2 and 5, as kinetic studies
indicated. Docking experiments suggested
that certain derivatives 5 and 6 may
efficiently fit into an allosteric site
positioned between the β-sheet including
Leu71 and Lys73 and a lipophilic pocket
closed by the loop consisting of Pro210 to
Leu 204. In cellular assays, several of
these new 4-thiazolidinone derivatives
showed insulinomimetic and
anti-inflammatory properties. Out of them,
compound 5b exhibited the most promising
profile, being able to promote the
activation of both insulin receptor and
downstream Akt protein as well as to
increase 2-deoxyglucose cellular uptake.
Interestingly, compound 5b was also able
to interrupt critical events in
inflammatory signalling.},
keywords = {Protein tyrosine phosphatases Enzyme
inhibitors Insulinomimetic effects
Anti-inflammatory activity Molecular
docking 5-Arylidene-4-thiazolidinone
derivatives},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2016.10.063},
url = {http://www.sciencedirect.com/science/article/pii/S0223523416309345
http://ac.els-cdn.com/S0223523416309345/1-s2.0-S0223523416309345-main.pdf?_tid= 72e236fe-ed3b-11e6-8bc2-00000aab0f6c&acdnat=1486475206_d6dd5764eee03f4148356c005814f688},
year = {2017},
type = {Journal Article}
}
x
Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents
New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated. Docking experiments suggested that certain derivatives 5 and 6 may efficiently fit into an allosteric site positioned between the β-sheet including Leu71 and Lys73 and a lipophilic pocket closed by the loop consisting of Pro210 to Leu 204. In cellular assays, several of these new 4-thiazolidinone derivatives showed insulinomimetic and anti-inflammatory properties. Out of them, compound 5b exhibited the most promising profile, being able to promote the activation of both insulin receptor and downstream Akt protein as well as to increase 2-deoxyglucose cellular uptake. Interestingly, compound 5b was also able to interrupt critical events in inflammatory signalling.
F. Sanz, F. Pognan, T. Steger-Hartmann, C. Díaz, M. Cases, M. Pastor, P. Marc, J. Wichard, K. Briggs, D. K. Watson, T. Kleinöder, C. Yang, A. Amberg, M. Beaumont, A. J. Brookes, S. Brunak, M. T. D. Cronin, G. F. Ecker, S. Escher, N. Greene, A. Guzmán, A. Hersey, P. Jacques, L. Lammens, J. Mestres, W. Muster, H. Northeved, M. Pinches, J. Saiz, N. Sajot, A. Valencia, J. van der Lei, N. P. E. Vermeulen, E. Vock, G. Wolber, and I. Zamora. Legacy data sharing to improve drug safety assessment: the eTOX project, Nat Rev Drug Discov, 16:811, 2017.
Links:
[doi:10.1038/nrd.2017.177]
[show BibTeX]
x
@article{RN250,
author = {Sanz, Ferran and Pognan, François and
Steger-Hartmann, Thomas and Díaz, Carlos
and Cases, Montserrat and Pastor, Manuel
and Marc, Philippe and Wichard, Joerg and
Briggs, Katharine and Watson, David K. and
Kleinöder, Thomas and Yang, Chihae and
Amberg, Alexander and Beaumont, Maria and
Brookes, Anthony J. and Brunak, Søren and
Cronin, Mark T. D. and Ecker, Gerhard F.
and Escher, Sylvia and Greene, Nigel and
Guzmán, Antonio and Hersey, Anne and
Jacques, Pascale and Lammens, Lieve and
Mestres, Jordi and Muster, Wolfgang and
Northeved, Helle and Pinches, Marc and
Saiz, Javier and Sajot, Nicolas and
Valencia, Alfonso and van der Lei, Johan
and Vermeulen, Nico P. E. and Vock, Esther
and Wolber, Gerhard and Zamora, Ismael},
title = {Legacy data sharing to improve drug
safety assessment: the eTOX project},
journal = {Nature Reviews Drug Discovery},
volume = {16},
pages = {811},
DOI = {10.1038/nrd.2017.177},
url = {http://dx.doi.org/10.1038/nrd.2017.177
http://www.nature.com/articles/nrd.2017.177.pdf},
year = {2017},
type = {Journal Article}
}
D. Schaller, S. Hagenow, G. Alpert, A. Naß, R. Schulz, M. Bermudez, H. Stark, and G. Wolber. Systematic data mining reveals synergistic H3R/MCHR1 ligands, ACS Medicinal Chemistry Letters, 8(6):648-653, 2017.
Links:
[doi:10.1021/acsmedchemlett.7b00118]
[show BibTeX]
[show abstract]
x
@article{RN202,
author = {Schaller, David and Hagenow, Stefanie and
Alpert, Gina and Naß, Alexandra and
Schulz, Robert and Bermudez, Marcel and
Stark, Holger and Wolber, Gerhard},
title = {Systematic data mining reveals
synergistic H3R/MCHR1 ligands},
journal = {ACS Medicinal Chemistry Letters},
volume = {8},
number = {6},
pages = {648-653},
abstract = {In this study, we report a ligand-centric
data mining approach that guided the
identification of suitable target profiles
for treating obesity. The newly developed
method is based on identifying target
pairs for synergistic positive effects and
also encompasses the exclusion of
compounds showing a detrimental effect on
obesity treatment (off-targets). Ligands
with known activity against
obesity-relevant targets were compared
using fingerprint representations. Similar
compounds with activities to different
targets were evaluated for the mechanism
of action since activation or deactivation
of drug targets determines the
pharmacological effect. In vitro
validation of the modeling results
revealed that three known modulators of
melanin-concentrating hormone receptor 1
(MCHR1) show a previously unknown
submicromolar affinity to the histamine H3
receptor (H3R). This synergistic activity
may present a novel therapeutic option
against obesity.},
keywords = {gpcr},
DOI = {10.1021/acsmedchemlett.7b00118},
url = {http://dx.doi.org/10.1021/acsmedchemlett.7b00118
http://pubs.acs.org/doi/pdfplus/10.1021/acsmedchemlett.7b00118},
year = {2017},
type = {Journal Article}
}
x
Systematic data mining reveals synergistic H3R/MCHR1 ligands
In this study, we report a ligand-centric data mining approach that guided the identification of suitable target profiles for treating obesity. The newly developed method is based on identifying target pairs for synergistic positive effects and also encompasses the exclusion of compounds showing a detrimental effect on obesity treatment (off-targets). Ligands with known activity against obesity-relevant targets were compared using fingerprint representations. Similar compounds with activities to different targets were evaluated for the mechanism of action since activation or deactivation of drug targets determines the pharmacological effect. In vitro validation of the modeling results revealed that three known modulators of melanin-concentrating hormone receptor 1 (MCHR1) show a previously unknown submicromolar affinity to the histamine H3 receptor (H3R). This synergistic activity may present a novel therapeutic option against obesity.
Q. Yan, D. Machalz, A. Zöllner, E. J. Sorensen, G. Wolber, and M. Bureik. Efficient substrate screening and inhibitor testing of human CYP4Z1 using permeabilized recombinant fission yeast, Biochem Pharmacol, 146:174-187, 2017.
Links:
[doi:10.1016/j.bcp.2017.09.011]
[show BibTeX]
[show abstract]
x
@article{RN206,
author = {Yan, Qi and Machalz, David and Zöllner,
Andy and Sorensen, Erik J. and Wolber,
Gerhard and Bureik, Matthias},
title = {Efficient substrate screening and
inhibitor testing of human CYP4Z1 using
permeabilized recombinant fission yeast},
journal = {Biochemical Pharmacology},
volume = {146},
pages = {174-187},
abstract = {We have established a protocol for the
preparation of permeabilized fission yeast
cells (enzyme bags) that recombinantly
express human cytochrome P450 enzymes
(CYPs). A direct comparison of CYP3A4
activity gave an eightfold higher
space-time yield for enzyme bag-catalyzed
biotransformation as compared to
whole-cell biotransformation, even though
the total number of cells employed was
lower by a factor of 150.
Biotransformation of the luminogenic
substrate Luciferin-H using
CYP2C9-containing enzyme bags proceeded
efficiently and stably for 24h. CYP4Z1 is
of interest because it is strongly
overexpressed both in breast cancer cells
and in breast cancer metastases; however,
current knowledge about its catalytic
properties is very limited. Screening of
CYP4Z1-containing enzyme bags with 15
luminogenic substrates enabled us to
identify two new hydroxylations and eleven
ether cleavage reactions that are
catalyzed by CYP4Z1. By far the best
substrate found in this study was
Luciferin benzyl ether (Luciferin-BE). On
the basis of the recently published
crystal structure of CYP4B1 we created a
new homology model of CYP4Z1 and performed
molecular docking experiments, which
indicate that all active substrates show a
highly similar binding geometry compared
to the endogenous substrates. The model
predicts that Ser113, Ser222, Asn381, and
Ser383 are key hydrogen bonding residues.
We also identified five new inhibitors of
CYP4Z1: miconazole, econazole,
aminobenzotriazole, tolazoline, and
1-benzylimidazole respectively, with the
last compound being the most potent giving
an IC50 value of 180nM in our test
system.},
keywords = {Human cytochrome P450 Biotransformation
Fission yeast Hydroxylation Ether
cleavage},
ISSN = {0006-2952},
DOI = {10.1016/j.bcp.2017.09.011},
url = {http://www.sciencedirect.com/science/article/pii/S000629521730607X},
year = {2017},
type = {Journal Article}
}
x
Efficient substrate screening and inhibitor testing of human CYP4Z1 using permeabilized recombinant fission yeast
We have established a protocol for the preparation of permeabilized fission yeast cells (enzyme bags) that recombinantly express human cytochrome P450 enzymes (CYPs). A direct comparison of CYP3A4 activity gave an eightfold higher space-time yield for enzyme bag-catalyzed biotransformation as compared to whole-cell biotransformation, even though the total number of cells employed was lower by a factor of 150. Biotransformation of the luminogenic substrate Luciferin-H using CYP2C9-containing enzyme bags proceeded efficiently and stably for 24h. CYP4Z1 is of interest because it is strongly overexpressed both in breast cancer cells and in breast cancer metastases; however, current knowledge about its catalytic properties is very limited. Screening of CYP4Z1-containing enzyme bags with 15 luminogenic substrates enabled us to identify two new hydroxylations and eleven ether cleavage reactions that are catalyzed by CYP4Z1. By far the best substrate found in this study was Luciferin benzyl ether (Luciferin-BE). On the basis of the recently published crystal structure of CYP4B1 we created a new homology model of CYP4Z1 and performed molecular docking experiments, which indicate that all active substrates show a highly similar binding geometry compared to the endogenous substrates. The model predicts that Ser113, Ser222, Asn381, and Ser383 are key hydrogen bonding residues. We also identified five new inhibitors of CYP4Z1: miconazole, econazole, aminobenzotriazole, tolazoline, and 1-benzylimidazole respectively, with the last compound being the most potent giving an IC50 value of 180nM in our test system.
J. Al-Asri, G. Gyémánt, E. Fazekas, G. Lehoczki, M. F. Melzig, G. Wolber, and J. Mortier. α-Amylase Modulation: Discovery of Inhibitors Using a Multi-Pharmacophore Approach for Virtual Screening, ChemMedChem, 11(21):2372-2377, 2016.
Links:
[doi:10.1002/cmdc.201600427]
[show BibTeX]
[show abstract]
x
@article{RN200,
author = {Al-Asri, Jamil and Gyémánt, Gyöngyi
and Fazekas, Erika and Lehoczki, Gábor
and Melzig, Matthias F. and Wolber,
Gerhard and Mortier, Jérémie},
title = {α-Amylase Modulation: Discovery of
Inhibitors Using a Multi-Pharmacophore
Approach for Virtual Screening},
journal = {ChemMedChem},
volume = {11},
number = {21},
pages = {2372-2377},
abstract = {Better control of postprandial
hyperglycemia can be achieved by delaying
the absorption of glucose resulting from
carbohydrate digestion. Because α-amylase
initiates the hydrolysis of
polysaccharides, the design of α-amylase
inhibitors can lead to the development of
new treatments for metabolic disorders
such as type II diabetes and obesity. In
this study, a rational computer-aided
approach was developed to identify novel
α-amylase inhibitors. Three-dimensional
pharmacophores were developed based on the
binding mode analysis of six different
families of compounds that bind to this
enzyme. In a stepwise virtual screening
workflow, seven molecules were selected
from a library of 1.4 million. Five out of
seven biologically tested compounds showed
α-amylase inhibition, and the two most
potent compounds inhibited α-amylase with
IC50 values of 17 and 27 μm. The
scaffold benzylideneacetohydrazide was
shared by four of the discovered
inhibitors, emerging as a novel drug-like
non-carbohydrate fragment and constituting
a promising lead scaffold for α-amylase
inhibition.},
keywords = {α-amylase computer-aided drug design
diabetes high-throughput virtual screening
lead discovery obesity},
ISSN = {1860-7187},
DOI = {10.1002/cmdc.201600427},
url = {http://dx.doi.org/10.1002/cmdc.201600427
http://onlinelibrary.wiley.com/store/10.1002/cmdc.201600427/asset/cmdc201600427.pdf?v= 1&t=iw6bvytr&s=b1ae9a27fb0f290b45c6a6997a8a3e9dff7b9678},
year = {2016},
type = {Journal Article}
}
x
α-Amylase Modulation: Discovery of Inhibitors Using a Multi-Pharmacophore Approach for Virtual Screening
Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α-amylase initiates the hydrolysis of polysaccharides, the design of α-amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer-aided approach was developed to identify novel α-amylase inhibitors. Three-dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme. In a stepwise virtual screening workflow, seven molecules were selected from a library of 1.4 million. Five out of seven biologically tested compounds showed α-amylase inhibition, and the two most potent compounds inhibited α-amylase with IC50 values of 17 and 27 μm. The scaffold benzylideneacetohydrazide was shared by four of the discovered inhibitors, emerging as a novel drug-like non-carbohydrate fragment and constituting a promising lead scaffold for α-amylase inhibition.
D. Becker, Z. Kaczmarska, C. Arkona, R. Schulz, C. Tauber, G. Wolber, R. Hilgenfeld, M. Coll, and J. Rademann. Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments, Nat Commun, 7:12761, 2016.
Links:
[doi:10.1038/ncomms12761]
[show BibTeX]
x
@article{RN198,
author = {Becker, Daniel and Kaczmarska, Zuzanna
and Arkona, Christoph and Schulz, Robert
and Tauber, Carolin and Wolber, Gerhard
and Hilgenfeld, Rolf and Coll, Miquel and
Rademann, Jörg},
title = {Irreversible inhibitors of the 3C
protease of Coxsackie virus through
templated assembly of protein-binding
fragments},
journal = {Nature Communications},
volume = {7},
pages = {12761},
DOI = {10.1038/ncomms12761},
url = {http://dx.doi.org/10.1038/ncomms12761
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052702/pdf/ncomms12761.pdf},
year = {2016},
type = {Journal Article}
}
M. Bermudez, J. Mortier, C. Rakers, D. Sydow, and G. Wolber. More than a look into a crystal ball: protein structure elucidation guided by molecular dynamics simulations, Drug Discov Today, 21(11):1799-1805, 2016.
Links:
[doi:10.1016/j.drudis.2016.07.001]
[show BibTeX]
[show abstract]
x
@article{RN193,
author = {Bermudez, Marcel and Mortier, Jeremie and
Rakers, Christin and Sydow, Dominique and
Wolber, Gerhard},
title = {More than a look into a crystal ball:
protein structure elucidation guided by
molecular dynamics simulations},
journal = {Drug Discovery Today},
volume = {21},
number = {11},
pages = {1799-1805},
abstract = {The ‘form follows function’ principle
implies that a structural determination of
protein structures is indispensable to
understand proteins in their biological
roles. However, experimental methods still
show shortcomings in the description of
the dynamic properties of proteins.
Therefore, molecular dynamics (MD)
simulations represent an essential tool
for structural biology to investigate
proteins as flexible and dynamic entities.
Here, we will give an overview on the
impact of MD simulations on structural
investigations, including studies that aim
at a prediction of protein-folding
pathways, protein-assembly processes and
the sampling of conformational space by
computational means.},
ISSN = {1359-6446},
DOI = {10.1016/j.drudis.2016.07.001},
url = {http://www.sciencedirect.com/science/article/pii/S1359644616302513
https://pdf.sciencedirectassets.com/271275/1-s2.0-S1359644616X00128/1-s2.0-S1359644616302513/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQDpMFAxqO8i5cWwO8J2bidQOOPWWOgX2xYgjlCqnmYpKAIgMz6zEqJOOqjcysWG%2F%2BjDZIPEG4hPysl42TQ%2BxrkJgLgq2gMIQRACGgwwNTkwMDM1NDY4NjUiDMbVMeQJp%2BA6xuTeeiq3A5yGUmiSxbecX6zyK9C0u9d8FvveGrkPLG2bgf%2FLpoQrYo2WyvA%2BBWqUubZ%2F%2F2lzFcSTpeDFbT3qjC0N3gXJAnlrhfnB4HtdM5JkFOs7rk4T5uxWa2QB%2Bxrb0uGWp6C%2FKniuq6eBMiJ59EW8Qua9SC1HjapOsfuus9g5HoQTBdya%2B%2B93vPUyT1l6n3DvNF79aTePLdf4GzCoc3La3CqQwXZ%2Bv00XVVkSLXyHqEtn%2BKj4RqGYDx5vybmCYgNtuQnt%2F4u%2FKij1yfRzcl%2BKOheRiB2UBQBFkx%2BGRL%2BqBFLx23kYZU2PrVD4ZjQMMXyglfn7R41W1Ts944jcTs7eKtPEaIuwbGZFi3rfxU%2BBL%2BrhXsqDJMbPTE%2BrqYpk6xiwMVJaY6kJH62kCLazVZrQ49cjhJjxeJti4aqVRxjr4XOP%2FJ9EatP%2BZoD3q47yNzrS1dG3FcQOp6Rtx1LGD9QPU8GrLpoB2%2F%2BrydWuCVqCFWw5iNbyp05sWQsfmSpFEMzsvkKO%2FCw0bATpkHdkF6WOn0A1lXIOsI0cDUPAe1xWJ3L0KZySQ0UZUqXJ8Gw4v%2FTlL5BY%2FUxSnor26xYwn6aO6wU6tAHBqopuW5pcz%2FJI%2BrCyUdYGVL8ZGUcN9osxZNHlsdHl%2FPSb5Ey3HqdiHTks1pszrFK8F0ZxsQNCYajkgKT3SAzhgrTmaNYfXyzLVkl3rMbW5QA0SqgsnR79JfHgUXuHGBnWyrsVF5mu9vmFjpTB4j2VqmtMOIjghMdHO%2FOIcR59ey2VTJQKE1Ulq0WJqECO72nl8nHMFEUoBLcWlCu5cwJlo5NxAcL7qC1hNPBzJlNFYMqU07s%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090752Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY5J43SP76%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=41d5423206e9b4da9d8bad5f7023e4f96b18b2664c923fbc9de439a7f34293c4&hash=218a0f350491d1c5c383f9505b728b13f7879d7491bb1fb18a042fb95213e569&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S1359644616302513&tid=spdf-4c8cdfd3-7d8d-4705-a232-8bf4948ce6eb&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2016},
type = {Journal Article}
}
x
More than a look into a crystal ball: protein structure elucidation guided by molecular dynamics simulations
The ‘form follows function’ principle implies that a structural determination of protein structures is indispensable to understand proteins in their biological roles. However, experimental methods still show shortcomings in the description of the dynamic properties of proteins. Therefore, molecular dynamics (MD) simulations represent an essential tool for structural biology to investigate proteins as flexible and dynamic entities. Here, we will give an overview on the impact of MD simulations on structural investigations, including studies that aim at a prediction of protein-folding pathways, protein-assembly processes and the sampling of conformational space by computational means.
A. Bock, M. Bermudez, F. Krebs, C. Matera, B. Chirinda, D. Sydow, C. Dallanoce, U. Holzgrabe, M. De Amici, M. J. Lohse, G. Wolber, and K. Mohr. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-Coupled Receptor, J Biol Chem, 291(31):16375-16389, 2016.
Links:
[doi:10.1074/jbc.M116.735431]
[show BibTeX]
[show abstract]
x
@article{RN197,
author = {Bock, Andreas and Bermudez, Marcel and
Krebs, Fabian and Matera, Carlo and
Chirinda, Brian and Sydow, Dominique and
Dallanoce, Clelia and Holzgrabe, Ulrike
and De Amici, Marco and Lohse, Martin J.
and Wolber, Gerhard and Mohr, Klaus},
title = {Ligand Binding Ensembles Determine Graded
Agonist Efficacies at a G Protein-Coupled
Receptor},
journal = {Journal of Biological Chemistry},
volume = {291},
number = {31},
pages = {16375-16389},
abstract = {G protein-coupled receptors constitute
the largest family of membrane receptors
and modulate almost every physiological
process in humans. Binding of agonists to
G protein-coupled receptors induces a
shift from inactive to active receptor
conformations. Biophysical studies of the
dynamic equilibrium of receptors suggest
that a portion of receptors can remain in
inactive states even in the presence of
saturating concentrations of agonist and G
protein mimetic. However, the molecular
details of agonist-bound inactive
receptors are poorly understood. Here we
use the model of bitopic
orthosteric/allosteric (i.e. dualsteric)
agonists for muscarinic M2 receptors to
demonstrate the existence and function of
such inactive agonist·receptor complexes
on a molecular level. Using all-atom
molecular dynamics simulations, dynophores
(i.e. a combination of static
three-dimensional pharmacophores and
molecular dynamics-based conformational
sampling), ligand design, and receptor
mutagenesis, we show that inactive
agonist·receptor complexes can result
from agonist binding to the allosteric
vestibule alone, whereas the dualsteric
binding mode produces active receptors.
Each agonist forms a distinct ligand
binding ensemble, and different agonist
efficacies depend on the fraction of
purely allosteric (i.e. inactive) versus
dualsteric (i.e. active) binding modes. We
propose that this concept may explain why
agonist·receptor complexes can be
inactive and that adopting multiple
binding modes may be generalized also to
small agonists where binding modes will be
only subtly different and confined to only
one binding site.},
keywords = {gpcr},
DOI = {10.1074/jbc.M116.735431},
url = {http://www.jbc.org/content/291/31/16375.abstract
http://www.jbc.org/content/291/31/16375.full.pdf},
year = {2016},
type = {Journal Article}
}
x
Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-Coupled Receptor
G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.
S. Bock, M. S. Murgueitio, G. Wolber, and G. Weindl. Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement, Pharmacol Res, 105:44-53, 2016.
Links:
[doi:10.1016/j.phrs.2016.01.016]
[show BibTeX]
[show abstract]
x
@article{RN183,
author = {Bock, Stephanie and Murgueitio, Manuela
S. and Wolber, Gerhard and Weindl,
Günther},
title = {Acute myeloid leukaemia-derived
Langerhans-like cells enhance Th1
polarization upon TLR2 engagement},
journal = {Pharmacological Research},
volume = {105},
pages = {44-53},
abstract = {Langerhans cells (LCs) represent a highly
specialized subset of epidermal dendritic
cells (DCs), yet not fully understood in
their function of balancing skin immunity.
Here, we investigated in vitro generated
Langerhans-like cells obtained from the
human acute myeloid leukaemia cell line
MUTZ-3 (MUTZ-LCs) to study TLR- and
cytokine-dependent activation of epidermal
DCs. MUTZ-LCs revealed high TLR2
expression and responded robustly to TLR2
engagement, confirmed by increased CD83,
CD86, PD-L1 and IDO expression,
upregulated IL-6, IL-12p40 and IL-23p19
mRNA levels IL-8 release. TLR2 activation
reduced CCR6 and elevated CCR7 mRNA
expression and induced migration of
MUTZ-LCs towards CCL21. Similar results
were obtained by stimulation with
pro-inflammatory cytokines TNF-α and
IL-1β whereas ligands of TLR3 and TLR4
failed to induce a fully mature phenotype.
Despite limited cytokine gene expression
and production for TLR2-activated
MUTZ-LCs, co-culture with naive CD4+ T
cells led to significantly increased
IFN-γ and IL-22 levels indicating Th1
differentiation independent of IL-12.
TLR2-mediated effects were blocked by the
putative TLR2/1 antagonist CU-CPT22,
however, no selectivity for either TLR2/1
or TLR2/6 was observed. Computer-aided
docking studies confirmed non-selective
binding of the TLR2 antagonist. Taken
together, our results indicate a critical
role for TLR2 signalling in MUTZ-LCs
considering the leukemic origin of the
generated Langerhans-like cells.},
keywords = {Acute myeloid leukaemia (AML) Langerhans
cells Toll-like receptors (TLR) TLR2
Pro-inflammatory cytokines T helper type 1
(Th1) cells},
ISSN = {1043-6618},
DOI = {10.1016/j.phrs.2016.01.016},
url = {http://www.sciencedirect.com/science/article/pii/S1043661816000220},
year = {2016},
type = {Journal Article}
}
x
Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement
Langerhans cells (LCs) represent a highly specialized subset of epidermal dendritic cells (DCs), yet not fully understood in their function of balancing skin immunity. Here, we investigated in vitro generated Langerhans-like cells obtained from the human acute myeloid leukaemia cell line MUTZ-3 (MUTZ-LCs) to study TLR- and cytokine-dependent activation of epidermal DCs. MUTZ-LCs revealed high TLR2 expression and responded robustly to TLR2 engagement, confirmed by increased CD83, CD86, PD-L1 and IDO expression, upregulated IL-6, IL-12p40 and IL-23p19 mRNA levels IL-8 release. TLR2 activation reduced CCR6 and elevated CCR7 mRNA expression and induced migration of MUTZ-LCs towards CCL21. Similar results were obtained by stimulation with pro-inflammatory cytokines TNF-α and IL-1β whereas ligands of TLR3 and TLR4 failed to induce a fully mature phenotype. Despite limited cytokine gene expression and production for TLR2-activated MUTZ-LCs, co-culture with naive CD4+ T cells led to significantly increased IFN-γ and IL-22 levels indicating Th1 differentiation independent of IL-12. TLR2-mediated effects were blocked by the putative TLR2/1 antagonist CU-CPT22, however, no selectivity for either TLR2/1 or TLR2/6 was observed. Computer-aided docking studies confirmed non-selective binding of the TLR2 antagonist. Taken together, our results indicate a critical role for TLR2 signalling in MUTZ-LCs considering the leukemic origin of the generated Langerhans-like cells.
E. Guerrieri, M. Bermudez, G. Wolber, I. P. Berzetei-Gurske, H. Schmidhammer, and M. Spetea. Structural determinants of diphenethylamines for interaction with the κ opioid receptor: Synthesis, pharmacology and molecular modeling studies, Bioorg Med Chem Lett, 26(19):4769-4774, 2016.
Links:
[doi:10.1016/j.bmcl.2016.08.031]
[show BibTeX]
[show abstract]
x
@article{RN191,
author = {Guerrieri, Elena and Bermudez, Marcel and
Wolber, Gerhard and Berzetei-Gurske, Ilona
P. and Schmidhammer, Helmut and Spetea,
Mariana},
title = {Structural determinants of
diphenethylamines for interaction with the
κ opioid receptor: Synthesis,
pharmacology and molecular modeling
studies},
journal = {Bioorganic & Medicinal Chemistry
Letters},
volume = {26},
number = {19},
pages = {4769-4774},
abstract = {The κ opioid (KOP) receptor crystal
structure in an inactive state offers
nowadays a valuable platform for inquiry
into receptor function. We describe the
synthesis, pharmacological evaluation and
docking calculations of KOP receptor
ligands from the class of
diphenethylamines using an active-like
structure of the KOP receptor attained by
molecular dynamics simulations. The
structure–activity relationships derived
from computational studies was in
accordance with pharmacological activities
of targeted diphenethylamines at the KOP
receptor established by competition
binding and G protein activation in vitro
assays. Our analysis identified that
agonist binding results in breaking of the
Arg156-Thr273 hydrogen bond, which
stabilizes the inactive receptor
conformation, and a crucial hydrogen bond
with His291 is formed. Compounds with a
phenolic 4-hydroxy group do not form the
hydrogen bond with His291, an important
residue for KOP affinity and agonist
activity. The size of the N-substituent
hosted by the hydrophobic pocket formed by
Val108, Ile316 and Tyr320 considerably
influences binding and selectivity, with
the n-alkyl size limit being five carbon
atoms, while bulky substituents turn KOP
agonists in antagonists. Thus, combination
of experimental and molecular modeling
strategies provides an initial framework
for understanding the structural features
of diphenethylamines that are essential to
promote binding affinity and selectivity
for the KOP receptor, and may be involved
in transduction of the ligand binding
event into molecular changes, ultimately
leading to receptor activation.},
keywords = {κ opioid receptor Diphenethylamine
Agonist Antagonist Partial agonist SAR
Molecular dynamics gpcr},
ISSN = {0960-894X},
DOI = {10.1016/j.bmcl.2016.08.031},
url = {http://www.sciencedirect.com/science/article/pii/S0960894X16308526
https://pdf.sciencedirectassets.com/271398/1-s2.0-S0960894X16X00182/1-s2.0-S0960894X16308526/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJGMEQCIBSuXR284U5c9bmAJSN5zVw47n5M5VTNwrBmGQ8hLXVcAiAWIgoCDAYq%2BrLMnoeOj0gcwMsJ%2BK2%2F2vx37jlwfG9V%2FiraAwhBEAIaDDA1OTAwMzU0Njg2NSIMjEBFMn9jIE9t1XN2KrcDLe7GRG%2FXcw3WEgKV9YXbSGYcHYB2z7r%2B9eRerOT0zpE0wRSFgQ%2FOH9BXlp37MIlzoDaMcVajFKZS8gcJXSICZZRdMHztkVCBW4DNZa%2BJxOwJ1E6Q6vzyyBGsc%2FRoV6Xba79A94ndoN8bYy6WNuplWyrl3mWsK2vv7sI6kqAQYvwZAuSo66P%2FLefOdgACsLXUvDUtMMpSN8TmoE6MAFh%2Fj9u1tN2PHd7Si9U0lR%2BPybWjyQIZhRLaPFiPA459dq%2F0DJYDW6PUXjnBlCqj2pjkDd8G%2FcrPGVCvjIs1dEukqNYRPh9wSQFFAb5Fi0wZV3zG%2F46Hc%2FeUQIprBOrsYtxFvQ1UWxSkaVfuuRD2NfJJC%2FoyWTyuxNmD0bdhukh9A21%2B1W83wJfu%2FecDVcxhN9MqXTDLroqrvl%2BRxWFnb%2BWbs%2B%2FV9bgL2cBI6AFt4X60UAEM%2FPSuYh%2FCMbaK1dtKiQLD4N%2F7kxQrpF%2BWzb6z4YOF5hW%2F4Jm%2BgH%2B0v9v9lego%2FcMGf98VdcRdShnMV0057mzmxPdKDL4AivAyKRRfnHrHbLoO1SdPlc41DKXR%2BjK0GtocjZ5j4aUAxDDnpo7rBTq1AThXMgqWLXhCysjiDb69KUDsmtirRuTrXpezLGPDfxkFp5ofIqWUR9J0yQNBLS%2BqlghqmfiGup4DJm90ED%2Bjr269Tuc2Ri4J0zfr7%2BcI1xixL%2Fy0rAQI30TJNbf1CsDGxfVixVDBG1Fkwa3KlpjjfAGAuGKaiPkPOMJuLo8YTbs28PVbbZSstkpcNX0npq661wJ6SM3c0BNDLzt2HCCzsKCoWT8MzDtnFnmY8Er2Z7ayg87lxx0%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090730Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYZNRZYJFV%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=037fa3ee2555131e64b8b5688e7e4a686e30cbef207e6458fb55f96764b245fb&hash=08167983ee3f84a7da97f9261f1c7a8c6d2025de5b3aa82b896df1eb7cd149b2&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960894X16308526&tid=spdf-8f3d8366-6e13-4767-a6f4-96592d64c57f&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2016},
type = {Journal Article}
}
x
Structural determinants of diphenethylamines for interaction with the κ opioid receptor: Synthesis, pharmacology and molecular modeling studies
The κ opioid (KOP) receptor crystal structure in an inactive state offers nowadays a valuable platform for inquiry into receptor function. We describe the synthesis, pharmacological evaluation and docking calculations of KOP receptor ligands from the class of diphenethylamines using an active-like structure of the KOP receptor attained by molecular dynamics simulations. The structure–activity relationships derived from computational studies was in accordance with pharmacological activities of targeted diphenethylamines at the KOP receptor established by competition binding and G protein activation in vitro assays. Our analysis identified that agonist binding results in breaking of the Arg156-Thr273 hydrogen bond, which stabilizes the inactive receptor conformation, and a crucial hydrogen bond with His291 is formed. Compounds with a phenolic 4-hydroxy group do not form the hydrogen bond with His291, an important residue for KOP affinity and agonist activity. The size of the N-substituent hosted by the hydrophobic pocket formed by Val108, Ile316 and Tyr320 considerably influences binding and selectivity, with the n-alkyl size limit being five carbon atoms, while bulky substituents turn KOP agonists in antagonists. Thus, combination of experimental and molecular modeling strategies provides an initial framework for understanding the structural features of diphenethylamines that are essential to promote binding affinity and selectivity for the KOP receptor, and may be involved in transduction of the ligand binding event into molecular changes, ultimately leading to receptor activation.
J. R. Homoki, A. Nemes, E. Fazekas, G. Gyémánt, P. Balogh, F. Gál, J. Al-Asri, J. Mortier, G. Wolber, L. Babinszky, and J. Remenyik. Anthocyanin composition, antioxidant efficiency, and α-amylase inhibitor activity of different Hungarian sour cherry varieties (Prunus cerasus L.), Food Chem, 194:222-229, 2016.
Links:
[doi:10.1016/j.foodchem.2015.07.130]
[show BibTeX]
[show abstract]
x
@article{RN177,
author = {Homoki, Judit R. and Nemes, Andrea and
Fazekas, Erika and Gyémánt, Gyöngyi and
Balogh, Péter and Gál, Ferenc and
Al-Asri, Jamil and Mortier, Jérémie and
Wolber, Gerhard and Babinszky, László
and Remenyik, Judit},
title = {Anthocyanin composition, antioxidant
efficiency, and α-amylase inhibitor
activity of different Hungarian sour
cherry varieties (Prunus cerasus L.)},
journal = {Food Chemistry},
volume = {194},
pages = {222-229},
abstract = {Five Hungarian sour cherry cultivars were
studied to determine their anthocyanin
contents and their possible inhibitory
properties. The water and methanol soluble
antioxidant capacities were separately
assessed by photoluminescence showing
values ranged from 3.4 μg mg−1 to 15.4
μg mg−1, respectively. The “VN1”
variety (selected from “Csengődi
csokros”) showed the highest antioxidant
capacity. The anthocyanin content,
measured by pH differential method or
isolated by solid phase extraction, was
the highest also in “VN1”. Correlation
was found between the anthocyanin content
and the high antioxidant capacity. The
main anthocyanin components were
cyanidin-3-O-rutinoside and
cyanidin-3-O-glucoside. The presence of
malvidin-3,5-O-diglycoside was verified by
MALDI-TOF MS. Sour cherry extracts and
selected anthocyanins inhibited the human
salivary alpha-amylase catalyzed
hydrolysis competitively. The lowest IC50
value, 55 μg mL−1 or 80 μM, was
measured for malvidin-3,5-O-diglycoside,
for which possible binding modes within
the alpha-amylase active site could be
investigated in silico using molecular
docking and molecular dynamics.},
keywords = {Sour cherry Antioxidants Anthocyanins
Human salivary α-amylase Inhibition},
ISSN = {0308-8146},
DOI = {10.1016/j.foodchem.2015.07.130},
url = {http://www.sciencedirect.com/science/article/pii/S0308814615011644
http://ac.els-cdn.com/S0308814615011644/1-s2.0-S0308814615011644-main.pdf?_tid= 626cf250-a00c-11e5-9e98-00000aacb35d&acdnat=1449841255_9edc44dca9e7c73085280f5fd716d846},
year = {2016},
type = {Journal Article}
}
x
Anthocyanin composition, antioxidant efficiency, and α-amylase inhibitor activity of different Hungarian sour cherry varieties (Prunus cerasus L.)
Five Hungarian sour cherry cultivars were studied to determine their anthocyanin contents and their possible inhibitory properties. The water and methanol soluble antioxidant capacities were separately assessed by photoluminescence showing values ranged from 3.4 μg mg−1 to 15.4 μg mg−1, respectively. The “VN1” variety (selected from “Csengődi csokros”) showed the highest antioxidant capacity. The anthocyanin content, measured by pH differential method or isolated by solid phase extraction, was the highest also in “VN1”. Correlation was found between the anthocyanin content and the high antioxidant capacity. The main anthocyanin components were cyanidin-3-O-rutinoside and cyanidin-3-O-glucoside. The presence of malvidin-3,5-O-diglycoside was verified by MALDI-TOF MS. Sour cherry extracts and selected anthocyanins inhibited the human salivary alpha-amylase catalyzed hydrolysis competitively. The lowest IC50 value, 55 μg mL−1 or 80 μM, was measured for malvidin-3,5-O-diglycoside, for which possible binding modes within the alpha-amylase active site could be investigated in silico using molecular docking and molecular dynamics.
S. Köhling, G. Künze, K. Lemmnitzer, M. Bermudez, G. Wolber, J. Schiller, D. Huster, and J. Rademann. Chemoenzymatic synthesis of nonasulfated tetrahyaluronan with a paramagnetic tag for studying its complex with Interleukin-10, Chemistry - A European Journal, 22(16): 5563-5574, 2016.
Links:
[doi:10.1002/chem.201504459]
[show BibTeX]
[show abstract]
x
@article{RN184,
author = {Köhling, Sebastian and Künze, Georg and
Lemmnitzer, Katharina and Bermudez, Marcel
and Wolber, Gerhard and Schiller, Jürgen
and Huster, Daniel and Rademann, Jörg},
title = {Chemoenzymatic synthesis of nonasulfated
tetrahyaluronan with a paramagnetic tag
for studying its complex with
Interleukin-10},
journal = {Chemistry - A European Journal},
volume = {22},
number = {16},
pages = { 5563-5574},
abstract = {Implants and artificial biomaterials
containing sulfated hyaluronans have been
shown to improve the healing of injured
skin and bones. It is hypothesized that
these effects are mediated by the binding
of sulfated glycosaminoglycans (GAGs) to
growth factors and cytokines, resulting in
the sequestering of proteins to the wound
healing site and in modulated protein
activity. Given that no direct synthetic
access to sulfated oligohyaluronans has
been available, little is known about
their protein binding and the structure of
the resulting protein complexes. Here, the
chemoenzymatic preparation of
oligohyaluronans on the gram scale is
described. Oligohyaluronans are converted
into anomeric azides at the reducing end,
enabling the attachment of analytical
labels through an anomeric ligation
reaction. A nonasulfated
tetrahyaluronan–ethylenediaminetetraacetic
acid derivative has been produced and used
as a paramagnetic tag for the elucidation
of the complex of this ligand with
interleukin-10 using paramagnetic
relaxation enhancement NMR analysis. The
metal ion position is resolved with
1.0 Å, enabling a refined structural
model of the complex.},
keywords = {carbohydrates cytokines growth factors
host–guest systems protein structures},
ISSN = {1521-3765},
DOI = {10.1002/chem.201504459},
url = {http://dx.doi.org/10.1002/chem.201504459
http://onlinelibrary.wiley.com/store/10.1002/chem.201504459/asset/chem201504459.pdf?v= 1&t=ili6eox1&s=58b1d54b76bcf28cf8559dcb069e2abdebc61887},
year = {2016},
type = {Journal Article}
}
x
Chemoenzymatic synthesis of nonasulfated tetrahyaluronan with a paramagnetic tag for studying its complex with Interleukin-10
Implants and artificial biomaterials containing sulfated hyaluronans have been shown to improve the healing of injured skin and bones. It is hypothesized that these effects are mediated by the binding of sulfated glycosaminoglycans (GAGs) to growth factors and cytokines, resulting in the sequestering of proteins to the wound healing site and in modulated protein activity. Given that no direct synthetic access to sulfated oligohyaluronans has been available, little is known about their protein binding and the structure of the resulting protein complexes. Here, the chemoenzymatic preparation of oligohyaluronans on the gram scale is described. Oligohyaluronans are converted into anomeric azides at the reducing end, enabling the attachment of analytical labels through an anomeric ligation reaction. A nonasulfated tetrahyaluronan–ethylenediaminetetraacetic acid derivative has been produced and used as a paramagnetic tag for the elucidation of the complex of this ligand with interleukin-10 using paramagnetic relaxation enhancement NMR analysis. The metal ion position is resolved with 1.0 Å, enabling a refined structural model of the complex.
B. Nizami, D. Sydow, G. Wolber, and B. Honarparvar. Molecular insight on the binding of NNRTI to K103N mutated HIV-1 RT: molecular dynamics simulations and dynamic pharmacophore analysis, Mol Biosyst, 12:3385-3395, 2016.
Links:
[doi:10.1039/C6MB00428H]
[show BibTeX]
x
@article{RN196,
author = {Nizami, Bilal and Sydow, Dominique and
Wolber, Gerhard and Honarparvar, Bahareh},
title = {Molecular insight on the binding of NNRTI
to K103N mutated HIV-1 RT: molecular
dynamics simulations and dynamic
pharmacophore analysis},
journal = {Molecular BioSystems},
volume = {12},
pages = {3385-3395},
DOI = {10.1039/C6MB00428H},
url = {https://pubs.rsc.org/en/content/articlepdf/2016/mb/c6mb00428h},
year = {2016},
type = {Journal Article}
}
V. Obermoser, M. E. Urban, M. S. Murgueitio, G. Wolber, U. Kintscher, and R. Gust. New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile, Eur J Med Chem, 124:138-152, 2016.
Links:
[doi:10.1016/j.ejmech.2016.08.027]
[show BibTeX]
[show abstract]
x
@article{RN194,
author = {Obermoser, Victoria and Urban, Margarethe
E. and Murgueitio, Manuela S. and Wolber,
Gerhard and Kintscher, Ulrich and Gust,
Ronald},
title = {New telmisartan-derived PPARγ agonists:
Impact of the 3D-binding mode on the
pharmacological profile},
journal = {European Journal of Medicinal Chemistry},
volume = {124},
pages = {138-152},
abstract = {In previous studies, the
4′-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic
acid was identified as pharmacophoric core
for PPARγ activation. In this
structure-activity relationship study the
C2-alkyl chain was elongated and the
2-COOH group was changed to a
carbamide/nitrile or shifted to the 3- or
4-position. Furthermore, the
benzo[d]imidazole was exchanged by
2,3-dihydrobenzo[d]thiazole or 1H-indole.
C2-propyl derivatives showed the profile
of partial agonists, while elongation of
the C2-chain to that of an n-heptyl group
or a 4-COOH shift changed the
pharmacological profile to that of a
potent full agonist. This finding can be
explained by binding to the LBD in
different ligand conformations. Two
anchoring points (Tyr473 and Arg288) exist
in the LBD, which have to be contacted to
achieve receptor activation. In a crystal
violet chemosensitivity assay using
COS-7 cells and LNCaP cells expressing
PPARγ only the carboxamide derivatives
influenced the cell growth, independently
on the presence of the PPARγ. Therefore,
receptor mediated cytotoxicity can be
excluded.},
keywords = {PPARγ Transactivation Cytotoxicity
Binding mode Molecular modeling},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2016.08.027},
url = {http://www.sciencedirect.com/science/article/pii/S0223523416306705
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year = {2016},
type = {Journal Article}
}
x
New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile
In previous studies, the 4′-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid was identified as pharmacophoric core for PPARγ activation. In this structure-activity relationship study the C2-alkyl chain was elongated and the 2-COOH group was changed to a carbamide/nitrile or shifted to the 3- or 4-position. Furthermore, the benzo[d]imidazole was exchanged by 2,3-dihydrobenzo[d]thiazole or 1H-indole. C2-propyl derivatives showed the profile of partial agonists, while elongation of the C2-chain to that of an n-heptyl group or a 4-COOH shift changed the pharmacological profile to that of a potent full agonist. This finding can be explained by binding to the LBD in different ligand conformations. Two anchoring points (Tyr473 and Arg288) exist in the LBD, which have to be contacted to achieve receptor activation. In a crystal violet chemosensitivity assay using COS-7 cells and LNCaP cells expressing PPARγ only the carboxamide derivatives influenced the cell growth, independently on the presence of the PPARγ. Therefore, receptor mediated cytotoxicity can be excluded.
C. Rakers, F. Schumacher, W. Meinl, H. Glatt, B. Kleuser, and G. Wolber. In silico prediction of human sulfotransferase 1E1 activity guided by pharmacophores from molecular dynamics simulations, J Biol Chem, 291(1):58-71, 2016.
Links:
[doi:10.1074/jbc.M115.685610]
[show BibTeX]
[show abstract]
x
@article{RN180,
author = {Rakers, Christin and Schumacher, Fabian
and Meinl, Walter and Glatt, Hansruedi and
Kleuser, Burkhard and Wolber, Gerhard},
title = {In silico prediction of human
sulfotransferase 1E1 activity guided by
pharmacophores from molecular dynamics
simulations},
journal = {Journal of Biological Chemistry},
volume = {291},
number = {1},
pages = {58-71},
abstract = {Acting during phase II metabolism,
sulfotransferases (SULTs) serve
detoxification by transforming a broad
spectrum of compounds from pharmaceutical,
nutritional, or environmental sources into
more easily excretable metabolites.
However, SULT activity has also been shown
to promote formation of reactive
metabolites that may have genotoxic
effects. SULT subtype 1E1 (SULT1E1) was
identified as a key player in estrogen
homeostasis, which is involved in many
physiological processes and the
pathogenesis of breast and endometrial
cancer. The development of an in silico
prediction model for SULT1E1 ligands would
therefore support the development of
metabolically inert drugs and help to
assess health risks related to hormonal
imbalances. Here, we report on a novel
approach to develop a model that enables
prediction of substrates and inhibitors of
SULT1E1. Molecular dynamics simulations
were performed to investigate enzyme
flexibility and sample protein
conformations. Pharmacophores were
developed that served as a cornerstone of
the model and machine learning techniques
were applied for prediction refinement.
The prediction model was used to screen
the DrugBank (a database of experimental
and approved drugs): 28 % of the predicted
hits were reported in literature as
ligands of SULT1E1. From the remaining
hits, a selection of nine molecules was
subjected to biochemical assay validation
and experimental results were in
accordance with the in silico prediction
of SULT1E1 inhibitors and substrates, thus
affirming our prediction hypotheses.},
DOI = {10.1074/jbc.M115.685610},
url = {http://www.jbc.org/content/early/2015/11/05/jbc.M115.685610.abstract
http://www.jbc.org/content/early/2015/11/05/jbc.M115.685610.full.pdf},
year = {2016},
type = {Journal Article}
}
x
In silico prediction of human sulfotransferase 1E1 activity guided by pharmacophores from molecular dynamics simulations
Acting during phase II metabolism, sulfotransferases (SULTs) serve detoxification by transforming a broad spectrum of compounds from pharmaceutical, nutritional, or environmental sources into more easily excretable metabolites. However, SULT activity has also been shown to promote formation of reactive metabolites that may have genotoxic effects. SULT subtype 1E1 (SULT1E1) was identified as a key player in estrogen homeostasis, which is involved in many physiological processes and the pathogenesis of breast and endometrial cancer. The development of an in silico prediction model for SULT1E1 ligands would therefore support the development of metabolically inert drugs and help to assess health risks related to hormonal imbalances. Here, we report on a novel approach to develop a model that enables prediction of substrates and inhibitors of SULT1E1. Molecular dynamics simulations were performed to investigate enzyme flexibility and sample protein conformations. Pharmacophores were developed that served as a cornerstone of the model and machine learning techniques were applied for prediction refinement. The prediction model was used to screen the DrugBank (a database of experimental and approved drugs): 28 % of the predicted hits were reported in literature as ligands of SULT1E1. From the remaining hits, a selection of nine molecules was subjected to biochemical assay validation and experimental results were in accordance with the in silico prediction of SULT1E1 inhibitors and substrates, thus affirming our prediction hypotheses.
J. Al-Asri, E. Fazekas, G. Lehoczki, A. Perdih, C. Görick, M. F. Melzig, G. Gyémánt, G. Wolber, and J. Mortier. From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors, Bioorg Med Chem, 23(20):6725-6732, 2015.
Links:
[doi:10.1016/j.bmc.2015.09.007]
[show BibTeX]
[show abstract]
x
@article{RN181,
author = {Al-Asri, Jamil and Fazekas, Erika and
Lehoczki, Gábor and Perdih, Andrej and
Görick, Cornelia and Melzig, Matthias F.
and Gyémánt, Gyöngyi and Wolber,
Gerhard and Mortier, Jérémie},
title = {From carbohydrates to drug-like
fragments: Rational development of novel
α-amylase inhibitors},
journal = {Bioorganic & Medicinal Chemistry},
volume = {23},
number = {20},
pages = {6725-6732},
abstract = {Starch catabolism leading to high glucose
level in blood is highly problematic in
chronic metabolic diseases, such as type
II diabetes and obesity. α-Amylase
catalyzes the hydrolysis of starch,
increasing blood sugar concentration. Its
inhibition represents a promising
therapeutic approach to control
hyperglycaemia. However, only few
drug-like molecule inhibitors without
sugar moieties have been discovered so
far, and little information on the
enzymatic mechanism is available. This
work aims at the discovery of novel small
α-amylase binders using a systematic in
silico methodology. 3D-pharmacophore-based
high throughput virtual screening of small
compounds libraries was performed to
identify compounds with high α-amylase
affinity. Twenty-seven compounds were
selected and biologically tested,
revealing IC50 values in the micromolar
range and ligand efficiency higher than
the one of the bound form of acarbose,
which is used as a reference for
α-amylase inhibition.},
keywords = {α-Amylase inhibition Fragment-based drug
design Virtual screening Pharmacophore
model Hyperglycaemia Obesity Type II
diabetes},
ISSN = {0968-0896},
DOI = {10.1016/j.bmc.2015.09.007},
url = {http://www.sciencedirect.com/science/article/pii/S0968089615300304
http://ac.els-cdn.com/S0968089615300304/1-s2.0-S0968089615300304-main.pdf?_tid= 975ce9ee-a00b-11e5-8116-00000aab0f6b&acdnat=1449840915_65cd6dd9bfdd7bab4bc7170cedef1f08},
year = {2015},
type = {Journal Article}
}
x
From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors
Starch catabolism leading to high glucose level in blood is highly problematic in chronic metabolic diseases, such as type II diabetes and obesity. α-Amylase catalyzes the hydrolysis of starch, increasing blood sugar concentration. Its inhibition represents a promising therapeutic approach to control hyperglycaemia. However, only few drug-like molecule inhibitors without sugar moieties have been discovered so far, and little information on the enzymatic mechanism is available. This work aims at the discovery of novel small α-amylase binders using a systematic in silico methodology. 3D-pharmacophore-based high throughput virtual screening of small compounds libraries was performed to identify compounds with high α-amylase affinity. Twenty-seven compounds were selected and biologically tested, revealing IC50 values in the micromolar range and ligand efficiency higher than the one of the bound form of acarbose, which is used as a reference for α-amylase inhibition.
M. Bermudez, C. Rakers, and G. Wolber. Structural characteristics of the allosteric binding site represent a key to subtype selective modulators of muscarinic acetylcholine receptors, Mol Inf, 34(8):526-530, 2015.
Links:
[doi:10.1002/minf.201500025]
[show BibTeX]
[show abstract]
x
@article{RN178,
author = {Bermudez, Marcel and Rakers, Christin and
Wolber, Gerhard},
title = {Structural characteristics of the
allosteric binding site represent a key to
subtype selective modulators of muscarinic
acetylcholine receptors},
journal = {Molecular Informatics},
volume = {34},
number = {8},
pages = {526-530},
abstract = {The high conservation of the orthosteric
acetylcholine binding site of muscarinic
receptors (MAChR) represents a
considerable challenge in terms of
designing subtype selective drugs. A
promising approach to gain subtype
selectivity is to include allosteric or
dualsteric targeting that aims to address
more specific extracellular binding sites.
Despite recent advances in crystallography
of G protein coupled receptors (GPCRs),
structural information for all 5 MAChR
subtypes is not yet available. Here we
report structural models of the active and
the inactive receptor state of all
subtypes derived by homology modelling in
combination with MD simulations. The
comparison of the allosteric binding site
unveils the characteristics for each
subtype on a structural level and
indicates anchor points for rational
design of selective drugs. Additionally,
homology models offer the possibility for
a rational explanation of dualsteric
subtype selectivity, as we show for the M2
over M5 selectivity of the dualsteric
ligands Atr-6-naph and Iper-6-phth.},
keywords = {Drug design Medicinal chemistry Molecular
dynamics Protein models Receptors gpcr},
ISSN = {1868-1751},
DOI = {10.1002/minf.201500025},
url = {http://dx.doi.org/10.1002/minf.201500025
http://onlinelibrary.wiley.com/store/10.1002/minf.201500025/asset/526_ftp.pdf?v= 1&t=ii1pqq6x&s=d5a558605b40783fdaa53e4c2a054424c9266926},
year = {2015},
type = {Journal Article}
}
x
Structural characteristics of the allosteric binding site represent a key to subtype selective modulators of muscarinic acetylcholine receptors
The high conservation of the orthosteric acetylcholine binding site of muscarinic receptors (MAChR) represents a considerable challenge in terms of designing subtype selective drugs. A promising approach to gain subtype selectivity is to include allosteric or dualsteric targeting that aims to address more specific extracellular binding sites. Despite recent advances in crystallography of G protein coupled receptors (GPCRs), structural information for all 5 MAChR subtypes is not yet available. Here we report structural models of the active and the inactive receptor state of all subtypes derived by homology modelling in combination with MD simulations. The comparison of the allosteric binding site unveils the characteristics for each subtype on a structural level and indicates anchor points for rational design of selective drugs. Additionally, homology models offer the possibility for a rational explanation of dualsteric subtype selectivity, as we show for the M2 over M5 selectivity of the dualsteric ligands Atr-6-naph and Iper-6-phth.
M. Bermudez, and G. Wolber. Structure vs. function - the impact of computational methods on the discovery of specific GPCR-ligands, Bioorg Med Chem, 23(14):3907-3912, 2015.
Links:
[doi:10.1016/j.bmc.2015.03.026]
[show BibTeX]
[show abstract]
x
@article{RN171,
author = {Bermudez, Marcel and Wolber, G.},
title = {Structure vs. function - the impact of
computational methods on the discovery of
specific GPCR-ligands},
journal = {Bioorganic & Medicinal Chemistry},
volume = {23},
number = {14},
pages = {3907-3912},
abstract = {Over the past decades, computational
methods have become invaluable for drug
design campaigns but also as auxiliary
tool for structural biology. The
combination of experimental and in silico
methods in the field of G protein coupled
receptors (GPCRs) is indispensable.
Despite recent groundbreaking achievements
in GPCR crystallography, structural
information for the vast majority of this
physiologically important protein class is
only accessible through homology models.
Since the understanding of the
conformational changes resulting in
multiple activation pathways is
incomplete, the design of specific GPCR
modulating drugs remains a major
challenge. However, due to the highly
interdisciplinary requirements for the
investigation of receptor function and the
necessity of joining scientist from
different fields, computational approaches
gain importance in rationalizing and
illustrating certain specific effects. In
silico methods, such as molecular dynamics
(MD) simulations, pharmacophore modeling
or docking, proved to be suitable to
complement experimental approaches. In
this review, we highlight recent examples
of in silico studies that were
successfully applied in the field of GPCR
research. Those approaches follow two main
goals: Firstly, structural investigations
that help to understand the receptor
function and the characterization of
ligand binding and secondly the
identification of novel GPCR modulators as
potential drugs.},
keywords = {gpcr},
DOI = {10.1016/j.bmc.2015.03.026},
url = {http://ac.els-cdn.com/S0968089615002102/1-s2.0-S0968089615002102-main.pdf?_tid=94b05366-a00b-11e5-866f-00000aacb35f&acdnat=1449840910_d9e103adde14b947c8c62833dffbd577},
year = {2015},
type = {Journal Article}
}
x
Structure vs. function - the impact of computational methods on the discovery of specific GPCR-ligands
Over the past decades, computational methods have become invaluable for drug design campaigns but also as auxiliary tool for structural biology. The combination of experimental and in silico methods in the field of G protein coupled receptors (GPCRs) is indispensable. Despite recent groundbreaking achievements in GPCR crystallography, structural information for the vast majority of this physiologically important protein class is only accessible through homology models. Since the understanding of the conformational changes resulting in multiple activation pathways is incomplete, the design of specific GPCR modulating drugs remains a major challenge. However, due to the highly interdisciplinary requirements for the investigation of receptor function and the necessity of joining scientist from different fields, computational approaches gain importance in rationalizing and illustrating certain specific effects. In silico methods, such as molecular dynamics (MD) simulations, pharmacophore modeling or docking, proved to be suitable to complement experimental approaches. In this review, we highlight recent examples of in silico studies that were successfully applied in the field of GPCR research. Those approaches follow two main goals: Firstly, structural investigations that help to understand the receptor function and the characterization of ligand binding and secondly the identification of novel GPCR modulators as potential drugs.
R. B. El-Houri, D. E. Kotowska, K. B. Christensen, S. Bhattacharya, N. Oksbjerg, G. Wolber, K. Kristiansen, and L. P. Christensen. Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes, Food & Function, 6(7):2135-44, 2015.
Links:
[doi:10.1039/C5FO00223K]
[show BibTeX]
[show abstract]
x
@article{RN175,
author = {El-Houri, Rime Bahij and Kotowska, Dorota
Ewa and Christensen, Kathrine Bisgaard and
Bhattacharya, Sumangala and Oksbjerg,
Niels and Wolber, Gerhard and Kristiansen,
Karsten and Christensen, Lars Porskjær},
title = {Polyacetylenes from carrots (Daucus
carota) improve glucose uptake in vitro in
adipocytes and myotubes},
journal = {Food & Function},
volume = {6},
number = {7},
pages = {2135-44},
abstract = {A dichloromethane (DCM) extract of carrot
roots was found to stimulate
insulin-dependent glucose uptake (GU) in
adipocytes in a dose dependent manner.
Bioassay-guided fractionation of the DCM
extract resulted in the isolation of the
polyacetylenes falcarinol and
falcarindiol. Both polyacetylenes were
able to significantly stimulate basal
and/or insulin-dependent GU in 3T3-L1
adipocytes and porcine myotube cell
cultures in a dose-dependent manner.
Falcarindiol increased peroxisome
proliferator-activated receptor
(PPAR)γ-mediated transactivation
significantly at concentrations of 3, 10
and 30 μM, while PPARγ-mediated
transactivation by falcarinol was only
observed at 10 μM. Docking studies
accordingly indicated that falcarindiol
binds to the ligand binding domain of
PPARγ with higher affinity than
falcarinol and that both polyacetylenes
exhibit characteristics of PPARγ partial
agonists. Falcarinol was shown to inhibit
adipocyte differentiation as evident by
gene expression studies and Oil Red O
staining, whereas falcarindiol did not
inhibit adipocyte differentiation, which
indicates that these polyacetylenes have
distinct modes of action. The results of
the present study suggest that falcarinol
and falcarindiol may represent scaffolds
for novel partial PPARγ agonists with
possible antidiabetic properties.},
DOI = {10.1039/C5FO00223K},
url = {http://pubs.rsc.org/en/content/articlepdf/2015/fo/c5fo00223k},
year = {2015},
type = {Journal Article}
}
x
Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes
A dichloromethane (DCM) extract of carrot roots was found to stimulate insulin-dependent glucose uptake (GU) in adipocytes in a dose dependent manner. Bioassay-guided fractionation of the DCM extract resulted in the isolation of the polyacetylenes falcarinol and falcarindiol. Both polyacetylenes were able to significantly stimulate basal and/or insulin-dependent GU in 3T3-L1 adipocytes and porcine myotube cell cultures in a dose-dependent manner. Falcarindiol increased peroxisome proliferator-activated receptor (PPAR)γ-mediated transactivation significantly at concentrations of 3, 10 and 30 μM, while PPARγ-mediated transactivation by falcarinol was only observed at 10 μM. Docking studies accordingly indicated that falcarindiol binds to the ligand binding domain of PPARγ with higher affinity than falcarinol and that both polyacetylenes exhibit characteristics of PPARγ partial agonists. Falcarinol was shown to inhibit adipocyte differentiation as evident by gene expression studies and Oil Red O staining, whereas falcarindiol did not inhibit adipocyte differentiation, which indicates that these polyacetylenes have distinct modes of action. The results of the present study suggest that falcarinol and falcarindiol may represent scaffolds for novel partial PPARγ agonists with possible antidiabetic properties.
R. B. El-Houri, J. Mortier, M. S. Murgueitio, G. Wolber, and L. P. Christensen. Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches, Planta Med, 81(06):488-494, 2015.
Links:
[doi:10.1055/s-0034-1383119]
[show BibTeX]
[show abstract]
x
@article{RN151,
author = {El-Houri, Rime B. and Mortier, Jérémie
and Murgueitio, Manuela S. and Wolber,
Gerhard and Christensen, Lars P.},
title = {Identification of PPARγ Agonists from
Natural Sources Using Different In Silico
Approaches},
journal = {Planta Medica},
volume = {81},
number = {06},
pages = {488-494},
abstract = {Peroxisome proliferator-activated
receptor γ plays an important role in
lipid and glucose homeostasis and is the
target of many drug discovery
investigations because of its role in
diseases such as type 2 diabetes.
Activation of peroxisome
proliferator-activated receptor γ by
agonists leads to a conformational change
in the ligand-binding domain altering the
transcription of several target genes
involved in glucose and lipid metabolism,
resulting in, for example, facilitation of
glucose and lipid uptake and amelioration
of insulin resistance, and other effects
that are important in the treatment of
type 2 diabetes. Peroxisome
proliferator-activated receptor γ partial
agonists are compounds with diminished
agonist efficacy compared to full
agonists; however, they maintain the
antidiabetic effect of full agonists but
do not induce the same magnitude of side
effects. This mini-review gives a short
introduction to in silico screening
methods and recent research advances using
computational approaches to identify
peroxisome proliferator-activated receptor
γ agonists, especially partial agonists,
from natural sources and how these ligands
bind to the peroxisome
proliferator-activated receptor γ in
order to better understand their
biological effects.},
ISSN = {0032-0943},
DOI = {10.1055/s-0034-1383119},
url = {https://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0034-1383119.pdf},
year = {2015},
type = {Journal Article}
}
x
Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches
Peroxisome proliferator-activated receptor γ plays an important role in lipid and glucose homeostasis and is the target of many drug discovery investigations because of its role in diseases such as type 2 diabetes. Activation of peroxisome proliferator-activated receptor γ by agonists leads to a conformational change in the ligand-binding domain altering the transcription of several target genes involved in glucose and lipid metabolism, resulting in, for example, facilitation of glucose and lipid uptake and amelioration of insulin resistance, and other effects that are important in the treatment of type 2 diabetes. Peroxisome proliferator-activated receptor γ partial agonists are compounds with diminished agonist efficacy compared to full agonists; however, they maintain the antidiabetic effect of full agonists but do not induce the same magnitude of side effects. This mini-review gives a short introduction to in silico screening methods and recent research advances using computational approaches to identify peroxisome proliferator-activated receptor γ agonists, especially partial agonists, from natural sources and how these ligands bind to the peroxisome proliferator-activated receptor γ in order to better understand their biological effects.
S. Grosskopf, C. Eckert, C. Arkona, S. Radetzki, K. Böhm, U. Heinemann, G. Wolber, J. v. Kries, W. Birchmeier, and J. Rademann. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in-vitro and in-vivo, ChemMedChem, 10(5):815-826, 2015.
Links:
[doi:10.1002/cmdc.201500015]
[show BibTeX]
[show abstract]
x
@article{RN172,
author = {Grosskopf, Stefanie and Eckert, Chris and
Arkona, Christoph and Radetzki, Silke and
Böhm, Kerstin and Heinemann, Udo and
Wolber, Gerhard and Kries, Jens-Peter von
and Birchmeier, Walter and Rademann,
Jörg},
title = {Selective inhibitors of the protein
tyrosine phosphatase SHP2 block cellular
motility and growth of cancer cells
in-vitro and in-vivo},
journal = {Chemmedchem},
volume = {10},
number = {5},
pages = {815-826},
abstract = {Selective inhibitors of the protein
tyrosine phosphatase SHP2 (PTPN11), an
enzyme, deregulated in numerous human
tumors, were generated by combination of
chemical synthesis with structure-based
rational design. 70
pyridazolon-4-ylidene-hydrazinyl-benzene
sulfonates were prepared and evaluated in
enzyme assays. Binding modes of active
inhibitors were simulated in silico using
a newly generated crystal structure of
SHP2. The most powerful molecule 25
(GS-493) inhibited SHP2 with an IC50 value
of 71 ± 15 nM in the enzyme assay and was
29- and 45-fold more active than against
related SHP1 and PTP1B. In cell culture
experiments 25 blocked HGF-stimulated
epithelial-mesenchymal transition of human
pancreatic tumor cells HPAF as indicated
by the reduction of minimum neighbor
distances of cells. Moreover, 25 inhibited
cell colony formation of the non-small
cell lung cancer cell line LXFA 526L in
soft agar. Finally, it inhibited tumor
growth in a murine xenograft model. Thus,
the novel specific molecule strengthens
the hypothesis that SHP2 is a relevant
protein target for the inhibition of
mobility and invasiveness of cancer
cells.},
DOI = {10.1002/cmdc.201500015},
url = {http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201500015/abstract
https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201500015},
year = {2015},
type = {Journal Article}
}
x
Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in-vitro and in-vivo
Selective inhibitors of the protein tyrosine phosphatase SHP2 (PTPN11), an enzyme, deregulated in numerous human tumors, were generated by combination of chemical synthesis with structure-based rational design. 70 pyridazolon-4-ylidene-hydrazinyl-benzene sulfonates were prepared and evaluated in enzyme assays. Binding modes of active inhibitors were simulated in silico using a newly generated crystal structure of SHP2. The most powerful molecule 25 (GS-493) inhibited SHP2 with an IC50 value of 71 ± 15 nM in the enzyme assay and was 29- and 45-fold more active than against related SHP1 and PTP1B. In cell culture experiments 25 blocked HGF-stimulated epithelial-mesenchymal transition of human pancreatic tumor cells HPAF as indicated by the reduction of minimum neighbor distances of cells. Moreover, 25 inhibited cell colony formation of the non-small cell lung cancer cell line LXFA 526L in soft agar. Finally, it inhibited tumor growth in a murine xenograft model. Thus, the novel specific molecule strengthens the hypothesis that SHP2 is a relevant protein target for the inhibition of mobility and invasiveness of cancer cells.
C. Meinguet, C. Bruyère, R. Frédérick, V. Mathieu, C. Vancraeynest, L. Pochet, J. Laloy, J. Mortier, G. Wolber, R. Kiss, B. Masereel, and J. Wouters. 3D-QSAR, design, synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties, Eur J Med Chem, 94:45-55, 2015.
Links:
[doi:10.1016/j.ejmech.2015.02.044]
[show BibTeX]
[show abstract]
x
@article{RN169,
author = {Meinguet, Céline and Bruyère, Céline
and Frédérick, Raphaël and Mathieu,
Véronique and Vancraeynest, Christelle
and Pochet, Lionel and Laloy, Julie and
Mortier, Jérémie and Wolber, Gerhard and
Kiss, Robert and Masereel, Bernard and
Wouters, Johan},
title = {3D-QSAR, design, synthesis and
characterization of trisubstituted harmine
derivatives with in vitro
antiproliferative properties},
journal = {European Journal of Medicinal Chemistry},
volume = {94},
pages = {45-55},
abstract = {Apolar trisubstituted derivatives of
harmine show high antiproliferative
activity on diverse cancer cell lines.
However, these molecules present a poor
solubility making these compounds poorly
bioavailable. Here, new compounds were
synthesized in order to improve solubility
while retaining antiproliferative
activity. First, polar substituents have
shown a higher solubility but a loss of
antiproliferative activity. Second, a
Comparative Molecular Field Analysis
(CoMFA) model was developed, guiding the
design and synthesis of eight new
compounds. Characterization has underlined
the in vitro antiproliferative character
of these compounds on five cancerous cell
lines, combining with a high solubility at
physiological pH, making these molecules
druggable. Moreover, targeting glioma
treatment, human intestinal absorption and
blood brain penetration have been
calculated, showing high absorption and
penetration properties.},
keywords = {Harmine derivatives Antiproliferative
activity Cytostatic activity Comparative
Molecular Field Analysis},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2015.02.044},
url = {http://www.sciencedirect.com/science/article/pii/S0223523415001403
http://ac.els-cdn.com/S0223523415001403/1-s2.0-S0223523415001403-main.pdf?_tid= f547ccae-c00a-11e4-8b31-00000aab0f01&acdnat=1425211582_cb6d118f6d7adec74c3f2a725b13dbdb},
year = {2015},
type = {Journal Article}
}
x
3D-QSAR, design, synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties
Apolar trisubstituted derivatives of harmine show high antiproliferative activity on diverse cancer cell lines. However, these molecules present a poor solubility making these compounds poorly bioavailable. Here, new compounds were synthesized in order to improve solubility while retaining antiproliferative activity. First, polar substituents have shown a higher solubility but a loss of antiproliferative activity. Second, a Comparative Molecular Field Analysis (CoMFA) model was developed, guiding the design and synthesis of eight new compounds. Characterization has underlined the in vitro antiproliferative character of these compounds on five cancerous cell lines, combining with a high solubility at physiological pH, making these molecules druggable. Moreover, targeting glioma treatment, human intestinal absorption and blood brain penetration have been calculated, showing high absorption and penetration properties.
J. Mortier, E. K. Nyakatura, O. Reimann, S. Huhmann, J. O. Daldrop, C. Baldauf, G. Wolber, M. S. Miettinen, and B. Koksch. Coiled-coils in phage display screening: Insight into exceptional selectivity provided by molecular dynamics, J Chem Inf Model, 55(3):495-500, 2015.
Links:
[doi:10.1021/ci500689c]
[show BibTeX]
[show abstract]
x
@article{RN160,
author = {Mortier, J. and Nyakatura, E. K. and
Reimann, O. and Huhmann, S. and Daldrop,
J. O. and Baldauf, C. and Wolber, G. and
Miettinen, M. S. and Koksch, B.},
title = {Coiled-coils in phage display screening:
Insight into exceptional selectivity
provided by molecular dynamics},
journal = {Journal of Chemical Information and
Modeling},
volume = {55},
number = {3},
pages = {495-500},
note = {Mortier, Jeremie Nyakatura, Elisabeth K
Reimann, Oliver Huhmann, Susanne Daldrop,
Jan O Baldauf, Carsten Wolber, Gerhard
Miettinen, Markus S Koksch, Beate ENG
2015/02/05 06:00 J Chem Inf Model. 2015
Feb 12.},
abstract = {Involved in numerous key biological
functions, protein helix-helix
interactions follow a well-defined
intermolecular recognition pattern. The
characteristic structure of the
alpha-helical coiled-coil allows for the
specific randomization of clearly defined
interaction partners within heteromeric
systems. In this work, a rationally
designed heterodimeric coiled-coil was
used to investigate potential factors
influencing the sequence selectivity in
interhelical interactions.},
ISSN = {1549-960X (Electronic) 1549-9596
(Linking)},
DOI = {10.1021/ci500689c},
url = {http://www.ncbi.nlm.nih.gov/pubmed/25648076
http://pubs.acs.org/doi/pdfplus/10.1021/ci500689c},
year = {2015},
type = {Journal Article}
}
x
Coiled-coils in phage display screening: Insight into exceptional selectivity provided by molecular dynamics
Involved in numerous key biological functions, protein helix-helix interactions follow a well-defined intermolecular recognition pattern. The characteristic structure of the alpha-helical coiled-coil allows for the specific randomization of clearly defined interaction partners within heteromeric systems. In this work, a rationally designed heterodimeric coiled-coil was used to investigate potential factors influencing the sequence selectivity in interhelical interactions.
J. Mortier, C. Rakers, M. Bermudez, M. S. Murgueitio, S. Riniker, and G. Wolber. The impact of molecular dynamics on drug design: applications for the characterization of ligand-macromolecule complexes, Drug Discov Today, 20(6):686-702, 2015.
Links:
[doi:10.1016/j.drudis.2015.01.003]
[show BibTeX]
[show abstract]
x
@article{RN162,
author = {Mortier, J. and Rakers, C. and Bermudez,
M. and Murgueitio, M. S. and Riniker, S.
and Wolber, G.},
title = {The impact of molecular dynamics on drug
design: applications for the
characterization of ligand-macromolecule
complexes},
journal = {Drug Discov Today},
volume = {20},
number = {6},
pages = {686-702},
note = {Mortier, Jeremie Rakers, Christin
Bermudez, Marcel Murgueitio, Manuela S
Riniker, Sereina Wolber, Gerhard ENG
REVIEW 2015/01/24 06:00 Drug Discov Today.
2015 Jan 20. pii: S1359-6446(15)00021-5.
doi: 10.1016/j.drudis.2015.01.003.},
abstract = {Among all tools available to design new
drugs, molecular dynamics (MD) simulations
have become an essential technique.
Initially developed to investigate
molecular models with a limited number of
atoms, computers now enable investigations
of large macromolecular systems with a
simulation time reaching the microsecond
range. The reviewed articles cover four
years of research to give an overview on
the actual impact of MD on the current
medicinal chemistry landscape with a
particular emphasis on studies of
ligand-protein interactions. With a
special focus on studies combining
computational approaches with data gained
from other techniques, this review shows
how deeply embedded MD simulations are in
drug design strategies and articulates
what the future of this technique could
be.},
keywords = {software},
ISSN = {1878-5832 (Electronic) 1359-6446
(Linking)},
DOI = {10.1016/j.drudis.2015.01.003},
url = {http://ac.els-cdn.com/S1359644615000215/1-s2.0-S1359644615000215-main.pdf?_tid=fd77aa3e-c00a-11e4-b562-00000aab0f6b&acdnat=1425211596_ad8df81890ab97631dd774ae4cbe1b41},
year = {2015},
type = {Journal Article}
}
x
The impact of molecular dynamics on drug design: applications for the characterization of ligand-macromolecule complexes
Among all tools available to design new drugs, molecular dynamics (MD) simulations have become an essential technique. Initially developed to investigate molecular models with a limited number of atoms, computers now enable investigations of large macromolecular systems with a simulation time reaching the microsecond range. The reviewed articles cover four years of research to give an overview on the actual impact of MD on the current medicinal chemistry landscape with a particular emphasis on studies of ligand-protein interactions. With a special focus on studies combining computational approaches with data gained from other techniques, this review shows how deeply embedded MD simulations are in drug design strategies and articulates what the future of this technique could be.
M. K. Parr, F. Botrè, A. Naß, J. Hengevoss, P. Diel, and G. Wolber. Ecdysteroids: A novel class of anabolic agents?, Biol Sport, 32(2):169-173, 2015.
Links:
[doi:10.5604/20831862.1144420]
[show BibTeX]
[show abstract]
x
@article{RN170,
author = {Parr, Maria Kristina and Botrè,
Francesco and Naß, Alexandra and
Hengevoss, Jonas and Diel, Patrick and
Wolber, Gerhard},
title = {Ecdysteroids: A novel class of anabolic
agents?},
journal = {Biology of Sport},
volume = {32},
number = {2},
pages = {169-173},
abstract = {Increasing numbers of dietary supplements
with ecdysteroids are marketed as "natural
anabolic agents". Results of recent
studies suggested that their anabolic
effect is mediated by estrogen receptor
(ER) binding. Within this study the
anabolic potency of ecdysterone was
compared to well characterized anabolic
substances. Effects on the fiber sizes of
the soleus muscle in rats as well the
diameter of C2C12 derived myotubes were
used as biological readouts. Ecdysterone
exhibited a strong hypertrophic effect on
the fiber size of rat soleus muscle that
was found even stronger compared to the
test compounds metandienone (dianabol),
estradienedione (trenbolox), and SARM S 1,
all administered in the same dose (5 mg/kg
body weight, for 21 days). In C2C12
myotubes ecdysterone (1 uM) induced a
significant increase of the diameter
comparable to dihydrotestosterone (1 uM)
and IGF 1 (1.3 nM). Molecular docking
experiments supported the ERβ mediated
action of ecdysterone. To clarify its
status in sports, ecdysterone should be
considered to be included in the class
"S1.2 Other Anabolic Agents" of the list
of prohibited substances of the World
Anti-Doping Agency.},
DOI = {10.5604/20831862.1144420},
url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447764/pdf/JBS-32-1144420.pdf},
year = {2015},
type = {Journal Article}
}
x
Ecdysteroids: A novel class of anabolic agents?
Increasing numbers of dietary supplements with ecdysteroids are marketed as "natural anabolic agents". Results of recent studies suggested that their anabolic effect is mediated by estrogen receptor (ER) binding. Within this study the anabolic potency of ecdysterone was compared to well characterized anabolic substances. Effects on the fiber sizes of the soleus muscle in rats as well the diameter of C2C12 derived myotubes were used as biological readouts. Ecdysterone exhibited a strong hypertrophic effect on the fiber size of rat soleus muscle that was found even stronger compared to the test compounds metandienone (dianabol), estradienedione (trenbolox), and SARM S 1, all administered in the same dose (5 mg/kg body weight, for 21 days). In C2C12 myotubes ecdysterone (1 uM) induced a significant increase of the diameter comparable to dihydrotestosterone (1 uM) and IGF 1 (1.3 nM). Molecular docking experiments supported the ERβ mediated action of ecdysterone. To clarify its status in sports, ecdysterone should be considered to be included in the class "S1.2 Other Anabolic Agents" of the list of prohibited substances of the World Anti-Doping Agency.
A. Perdih, M. Hrast, K. Pureber, H. Barreteau, S. Grdadolnik, D. Kocjan, S. Gobec, T. Solmajer, and G. Wolber. Furan-based benzene mono- and dicarboxylic acid derivatives as multiple inhibitors of the bacterial Mur ligases (MurC-MurF): experimental and computational characterization, J Comput Aided Mol Des, :1-20, 2015.
Links:
[doi:10.1007/s10822-015-9843-6]
[show BibTeX]
[show abstract]
x
@article{RN174,
author = {Perdih, Andrej and Hrast, Martina and
Pureber, Kaja and Barreteau, Hélène and
Grdadolnik, SimonaGolič and Kocjan, Darko
and Gobec, Stanislav and Solmajer, Tom and
Wolber, Gerhard},
title = {Furan-based benzene mono- and
dicarboxylic acid derivatives as multiple
inhibitors of the bacterial Mur ligases
(MurC-MurF): experimental and
computational characterization},
journal = {Journal of Computer-Aided Molecular
Design},
pages = {1-20},
abstract = {Bacterial resistance to the available
antibiotic agents underlines an urgent
need for the discovery of novel
antibacterial agents. Members of the
bacterial Mur ligase family MurC-MurF
involved in the intracellular stages of
the bacterial peptidoglycan biosynthesis
have recently emerged as a collection of
attractive targets for novel antibacterial
drug design. In this study, we have first
extended the knowledge of the class of
furan-based benzene-1,3-dicarboxylic acid
derivatives by first showing a multiple
MurC-MurF ligase inhibition for
representatives of the extended series of
this class. Steady-state kinetics studies
on the MurD enzyme were performed for
compound 1, suggesting a competitive
inhibition with respect to ATP. To the
best of our knowledge, compound 1
represents the first ATP-competitive MurD
inhibitor reported to date with concurrent
multiple inhibition of all four Mur
ligases (MurC-MurF). Subsequent molecular
dynamic (MD) simulations coupled with
interaction energy calculations were
performed for two alternative in silico
models of compound 1 in the UMA/D-Glu- and
ATP-binding sites of MurD, identifying
binding in the ATP-binding site as
energetically more favorable in comparison
to the UMA/D-Glu-binding site, which was
in agreement with steady-state kinetic
data. In the final stage, based on the
obtained MD data novel furan-based benzene
monocarboxylic acid derivatives 8-11,
exhibiting multiple Mur ligase (MurC-MurF)
inhibition with predominantly superior
ligase inhibition over the original
series, were discovered and for compound
10 it was shown to possess promising
antibacterial activity against S. aureus.
These compounds represent novel leads that
could by further optimization pave the way
to novel antibacterial agents. },
keywords = {Bacterial Mur (MurC–MurF) ligase
ATP-competitive inhibition Molecular
dynamics (MD) Steady-state kinetics
measurements Antibacterial agents Drug
design},
ISSN = {0920-654X},
DOI = {10.1007/s10822-015-9843-6},
url = {http://dx.doi.org/10.1007/s10822-015-9843-6
http://download.springer.com/static/pdf/718/art%253A10.1007%252Fs10822-015-9843-6.pdf?originUrl= http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs10822-015-9843-6&token2=exp=1444917652~acl=%2Fstatic%2Fpdf%2F718%2Fart%25253A10.1007%25252Fs10822-015-9843-6.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs10822-015-9843-6*~hmac=4f2c8e6a70f3ecc9b08f6110e685bc18eddcae8b3233d8a3acaff9ac2b51bdc2},
year = {2015},
type = {Journal Article}
}
x
Furan-based benzene mono- and dicarboxylic acid derivatives as multiple inhibitors of the bacterial Mur ligases (MurC-MurF): experimental and computational characterization
Bacterial resistance to the available antibiotic agents underlines an urgent need for the discovery of novel antibacterial agents. Members of the bacterial Mur ligase family MurC-MurF involved in the intracellular stages of the bacterial peptidoglycan biosynthesis have recently emerged as a collection of attractive targets for novel antibacterial drug design. In this study, we have first extended the knowledge of the class of furan-based benzene-1,3-dicarboxylic acid derivatives by first showing a multiple MurC-MurF ligase inhibition for representatives of the extended series of this class. Steady-state kinetics studies on the MurD enzyme were performed for compound 1, suggesting a competitive inhibition with respect to ATP. To the best of our knowledge, compound 1 represents the first ATP-competitive MurD inhibitor reported to date with concurrent multiple inhibition of all four Mur ligases (MurC-MurF). Subsequent molecular dynamic (MD) simulations coupled with interaction energy calculations were performed for two alternative in silico models of compound 1 in the UMA/D-Glu- and ATP-binding sites of MurD, identifying binding in the ATP-binding site as energetically more favorable in comparison to the UMA/D-Glu-binding site, which was in agreement with steady-state kinetic data. In the final stage, based on the obtained MD data novel furan-based benzene monocarboxylic acid derivatives 8-11, exhibiting multiple Mur ligase (MurC-MurF) inhibition with predominantly superior ligase inhibition over the original series, were discovered and for compound 10 it was shown to possess promising antibacterial activity against S. aureus. These compounds represent novel leads that could by further optimization pave the way to novel antibacterial agents.
C. Rakers, M. Bermudez, B. G. Keller, J. Mortier, and G. Wolber. Computational close up on protein-protein interactions: how to unravel the invisible using molecular dynamics simulations?, Wiley Interdisciplinary Reviews: Computational Molecular Science, 5(5):345-359, 2015.
Links:
[doi:10.1002/wcms.1222]
[show BibTeX]
[show abstract]
x
@article{RN176,
author = {Rakers, Christin and Bermudez, Marcel and
Keller, Bettina G. and Mortier, Jérémie
and Wolber, Gerhard},
title = {Computational close up on protein-protein
interactions: how to unravel the invisible
using molecular dynamics simulations?},
journal = {Wiley Interdisciplinary Reviews:
Computational Molecular Science},
volume = {5},
number = {5},
pages = {345-359},
abstract = {As an essential part of many biological
processes, protein–protein interactions
(PPIs) offer exciting and promising
opportunities for drug discovery by
extension of the druggable target space.
Over the last decade, studies on protein
networks have significantly increased the
number of identified PPIs. However,
despite steadily growing data on PPIs,
detailed understanding of the interaction
surfaces and their dynamics remains
limited. Furthermore, the development of
small‐molecule inhibitors of PPIs faces
technological challenges, leaving the
question about the ‘druggability’ of
PPIs open. Molecular dynamics (MD)
simulations may facilitate the prediction
of druggable binding sites on
protein–protein interfaces by detecting
binding hot spots and transient pockets.
MD allows for a detailed analysis of
structural and functional aspects of PPIs
and thus provides valuable insights into
PPI mechanisms and supports the design of
PPI modulators. We provide an overview on
the main areas of MD applications to PPIs
including structural investigations and
the design of PPI disruptors. Emphasizing
the beneficial synergies between
computational and experimental techniques,
MD techniques are also frequently applied
to low‐resolution structural data and
have been used to elucidate structure and
movements of complex macromolecular
structures relevant for biological
processes.},
DOI = {10.1002/wcms.1222},
url = {http://onlinelibrary.wiley.com/doi/10.1002/wcms.1222/abstract
http://onlinelibrary.wiley.com/store/10.1002/wcms.1222/asset/wcms1222.pdf?v= 1&t=ii1ppzby&s=c5ce7829a968b92bb67ba6f3cc35285d70cee2ca},
year = {2015},
type = {Journal Article}
}
x
Computational close up on protein-protein interactions: how to unravel the invisible using molecular dynamics simulations?
As an essential part of many biological processes, protein–protein interactions (PPIs) offer exciting and promising opportunities for drug discovery by extension of the druggable target space. Over the last decade, studies on protein networks have significantly increased the number of identified PPIs. However, despite steadily growing data on PPIs, detailed understanding of the interaction surfaces and their dynamics remains limited. Furthermore, the development of small‐molecule inhibitors of PPIs faces technological challenges, leaving the question about the ‘druggability’ of PPIs open. Molecular dynamics (MD) simulations may facilitate the prediction of druggable binding sites on protein–protein interfaces by detecting binding hot spots and transient pockets. MD allows for a detailed analysis of structural and functional aspects of PPIs and thus provides valuable insights into PPI mechanisms and supports the design of PPI modulators. We provide an overview on the main areas of MD applications to PPIs including structural investigations and the design of PPI disruptors. Emphasizing the beneficial synergies between computational and experimental techniques, MD techniques are also frequently applied to low‐resolution structural data and have been used to elucidate structure and movements of complex macromolecular structures relevant for biological processes.
V. Asante, J. Mortier, G. Wolber, and B. Koksch. Impact of fluorination on proteolytic stability of peptides: a case study with α-chymotrypsin and pepsin, Amino Acids, 46(12):2733-2744, 2014.
Links:
[doi:10.1007/s00726-014-1819-7]
[show BibTeX]
[show abstract]
x
@article{RN147,
author = {Asante, Vivian and Mortier, Jérémie and
Wolber, Gerhard and Koksch, Beate},
title = {Impact of fluorination on proteolytic
stability of peptides: a case study with
α-chymotrypsin and pepsin},
journal = {Amino Acids},
volume = {46},
number = {12},
pages = {2733-2744},
abstract = {Protease stability is a key consideration
in the development of peptide-based drugs.
A major approach to increase the
bioavailability of pharmacologically
active peptides is the incorporation of
non-natural amino acids. Due to the unique
properties of fluorine, fluorinated
organic molecules have proven useful in
the development of therapeutically active
small molecules as well as in materials
and crop science. This study presents data
on the ability of fluorinated amino acids
to influence proteolytic stability when
present in peptide sequences that are
based on ideal protease substrates.
Different model peptides containing
fluorinated amino acids or ethylglycine in
the P2, P1′or P2′ positions were
designed according to the specificities of
the serine protease, α-chymotrypsin (EC
3.4.21.1) or the aspartic protease, pepsin
(EC 3.4.23.1). The proteolytic stability
of the peptides toward these enzymes was
determined by an analytical RP-HPLC assay
with fluorescence detection and compared
to a control sequence. Molecular modeling
was used to support the interpretation of
the structure–activity relationship
based on the analysis of potential
ligand-enzyme interactions. Surprisingly,
an increase in proteolytic stability was
observed only in a few cases. Thus, this
systematic study shows that the
proteolytic stability of fluorinated
peptides is not predictable, but rather is
a very complex phenomenon that depends on
the particular enzyme, the position of the
substitution relative to the cleavage site
and the fluorine content of the side
chain.},
keywords = {Chymotrypsin Pepsin Aminobutyric acid
Difluoroethylglycine
Trifluoroethylglycine},
ISSN = {0939-4451},
DOI = {10.1007/s00726-014-1819-7},
year = {2014},
type = {Journal Article}
}
x
Impact of fluorination on proteolytic stability of peptides: a case study with α-chymotrypsin and pepsin
Protease stability is a key consideration in the development of peptide-based drugs. A major approach to increase the bioavailability of pharmacologically active peptides is the incorporation of non-natural amino acids. Due to the unique properties of fluorine, fluorinated organic molecules have proven useful in the development of therapeutically active small molecules as well as in materials and crop science. This study presents data on the ability of fluorinated amino acids to influence proteolytic stability when present in peptide sequences that are based on ideal protease substrates. Different model peptides containing fluorinated amino acids or ethylglycine in the P2, P1′or P2′ positions were designed according to the specificities of the serine protease, α-chymotrypsin (EC 3.4.21.1) or the aspartic protease, pepsin (EC 3.4.23.1). The proteolytic stability of the peptides toward these enzymes was determined by an analytical RP-HPLC assay with fluorescence detection and compared to a control sequence. Molecular modeling was used to support the interpretation of the structure–activity relationship based on the analysis of potential ligand-enzyme interactions. Surprisingly, an increase in proteolytic stability was observed only in a few cases. Thus, this systematic study shows that the proteolytic stability of fluorinated peptides is not predictable, but rather is a very complex phenomenon that depends on the particular enzyme, the position of the substitution relative to the cleavage site and the fluorine content of the side chain.
S. A. Galal, S. H. M. Khairat, F. A. F. Ragab, A. S. Abdelsamie, M. M. Ali, S. M. Soliman, J. Mortier, G. Wolber, and H. I. El Diwani. Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity, Eur J Med Chem, 86:122-132, 2014.
Links:
[doi:10.1016/j.ejmech.2014.08.048]
[show BibTeX]
[show abstract]
x
@article{RN152,
author = {Galal, Shadia A. and Khairat, Sarah H. M.
and Ragab, Fatma A. F. and Abdelsamie,
Ahmed S. and Ali, Mamdouh M. and Soliman,
Salwa M. and Mortier, Jérémie and
Wolber, Gerhard and El Diwani, Hoda I.},
title = {Design, synthesis and molecular docking
study of novel quinoxalin-2(1H)-ones as
anti-tumor active agents with inhibition
of tyrosine kinase receptor and studying
their cyclooxygenase-2 activity},
journal = {European Journal of Medicinal Chemistry},
volume = {86},
number = {0},
pages = {122-132},
abstract = {On continuation to our work, new
quinoxalin-2(1H)-ones were synthesized to
study their cytotoxic effect against
HepG-2 and MCF-7 with their effect on the
human tyrosine kinase (TRK). Compounds 12,
18, 15, 13, 11a, 20 and 16, respectively,
were found to be more potent than
cisplatin against HepG2 and selective to
TRK. Also, compounds 12, 18, 20, 13, 14,
and 22, respectively, exhibited decidedly
activity against MCF-7 and selectivity
against human TRK compared to cisplatin. A
molecular docking study was also performed
to gain comprehensive understanding into
plausible binding modes and to conclude
the structure activity relationships of
the synthesized compounds. Moreover,
anti-inflammatory activity was studied.
Compounds 12, 15, 18 and 22 were found to
be potent and selective against COX-2.},
keywords = {Synthesis Quinoxalines Antitumor activity
Cyclooxygenase-2 Docking Protein tyrosine
kinase},
ISSN = {0223-5234},
DOI = {10.1016/j.ejmech.2014.08.048},
url = {http://www.sciencedirect.com/science/article/pii/S0223523414007831
http://ac.els-cdn.com/S0223523414007831/1-s2.0-S0223523414007831-main.pdf?_tid= b482ad88-a00b-11e5-8f62-00000aacb361&acdnat=1449840963_a223020762d86fd4b9cb81d2db1509d5},
year = {2014},
type = {Journal Article}
}
x
Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity
On continuation to our work, new quinoxalin-2(1H)-ones were synthesized to study their cytotoxic effect against HepG-2 and MCF-7 with their effect on the human tyrosine kinase (TRK). Compounds 12, 18, 15, 13, 11a, 20 and 16, respectively, were found to be more potent than cisplatin against HepG2 and selective to TRK. Also, compounds 12, 18, 20, 13, 14, and 22, respectively, exhibited decidedly activity against MCF-7 and selectivity against human TRK compared to cisplatin. A molecular docking study was also performed to gain comprehensive understanding into plausible binding modes and to conclude the structure activity relationships of the synthesized compounds. Moreover, anti-inflammatory activity was studied. Compounds 12, 15, 18 and 22 were found to be potent and selective against COX-2.
D. Kotowska, R. B. El-Houri, K. Borkowski, R. K. Petersen, X. C. Fretté, G. Wolber, K. Grevsen, K. B. Christensen, L. P. Christensen, and K. Kristiansen. Isomeric C12-alkamides from the roots of Echinacea Purpurea improve basal and insulin-dependent glucose uptake in 3T3-L1 adipocytes, Planta Med, 80(18):1712-1720, 2014.
Links:
[doi:10.1055/s-0034-1383252]
[show BibTeX]
x
@article{RN155,
author = {Kotowska, Dorota and El-Houri, Rime B.
and Borkowski, Kamil and Petersen, Rasmus
K. and Fretté, Xavier C. and Wolber,
Gerhard and Grevsen, Kai and Christensen,
Kathrine B. and Christensen, Lars P. and
Kristiansen, Karsten},
title = {Isomeric C12-alkamides from the roots of
Echinacea Purpurea improve basal and
insulin-dependent glucose uptake in 3T3-L1
adipocytes},
journal = {Planta Medica},
volume = {80},
number = {18},
pages = {1712-1720},
ISSN = {0032-0943},
DOI = {10.1055/s-0034-1383252},
url = {https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0034-1383252.pdf},
year = {2014},
type = {Journal Article}
}
M. S. Murgueitio, P. Henneke, H. Glossmann, S. Santos-Sierra, and G. Wolber. Prospective virtual screening in a sparse data scenario: design of small-molecule TLR2 antagonists, ChemMedChem, 9(4):813-822, 2014.
Links:
[doi:10.1002/Cmdc.201300445]
[show BibTeX]
[show abstract]
x
@article{RN3,
author = {Murgueitio, M. S. and Henneke, P. and
Glossmann, H. and Santos-Sierra, S. and
Wolber, G.},
title = {Prospective virtual screening in a sparse
data scenario: design of small-molecule
TLR2 antagonists},
journal = {Chemmedchem},
volume = {9},
number = {4},
pages = {813-822},
note = {Ae1se Times Cited:0 Cited References
Count:36},
abstract = {Toll-like receptors (TLRs) are critical
signaling molecules with roles in various
severe clinical conditions such as sepsis
and rheumatoid arthritis, and have
therefore been advocated as promising drug
targets for the treatment of these
diseases. The aim of this study was to
discover small-molecule antagonists of
TLR2 by computer-aided drug design. This
goal poses several challenges due to the
lack of available data on TLR2 modulators.
To overcome these hurdles we developed a
combined structure- and ligand-based
virtual screening approach. First, we
calculated molecular interaction fields of
the TLR2 binding site to derive a
structure-based 3D pharmacophore, which
was then used for virtual screening. We
then performed a two-step shape- and
feature-based similarity search using
known TLR2 ligands as query structures. A
selection of virtual screening hits was
biologically tested in a cell-based assay
for TLR2 signaling inhibition, leading to
the identification of several compounds
with antagonistic activity (IC50 values)
in the low-micromolar range.},
keywords = {drug discovery receptors tlr2 antagonists
toll-like receptors virtual screening
toll-like receptors pattern-recognition
receptors pathogen recognition conformer
generation structural biology innate
immunity binding-sites shape
pharmacophores discovery},
ISSN = {1860-7179},
DOI = {10.1002/Cmdc.201300445},
url = {Go to ISI://WOS:000333749200017
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300445/abstract
https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201300445},
year = {2014},
type = {Journal Article}
}
x
Prospective virtual screening in a sparse data scenario: design of small-molecule TLR2 antagonists
Toll-like receptors (TLRs) are critical signaling molecules with roles in various severe clinical conditions such as sepsis and rheumatoid arthritis, and have therefore been advocated as promising drug targets for the treatment of these diseases. The aim of this study was to discover small-molecule antagonists of TLR2 by computer-aided drug design. This goal poses several challenges due to the lack of available data on TLR2 modulators. To overcome these hurdles we developed a combined structure- and ligand-based virtual screening approach. First, we calculated molecular interaction fields of the TLR2 binding site to derive a structure-based 3D pharmacophore, which was then used for virtual screening. We then performed a two-step shape- and feature-based similarity search using known TLR2 ligands as query structures. A selection of virtual screening hits was biologically tested in a cell-based assay for TLR2 signaling inhibition, leading to the identification of several compounds with antagonistic activity (IC50 values) in the low-micromolar range.
E. K. Nyakatura, R. R. Araghi, J. Mortier, S. Wieczorek, C. Baldauf, G. Wolber, and B. Koksch. An unusual interstrand h-bond stabilizes the heteroassembly of helical alpha beta gamma-chimeras with natural peptides, ACS Chem Biol, 9(3):613-616, 2014.
Links:
[doi:10.1021/Cb4007979]
[show BibTeX]
[show abstract]
x
@article{RN6,
author = {Nyakatura, E. K. and Araghi, R. R. and
Mortier, J. and Wieczorek, S. and Baldauf,
C. and Wolber, G. and Koksch, B.},
title = {An unusual interstrand h-bond stabilizes
the heteroassembly of helical alpha beta
gamma-chimeras with natural peptides},
journal = {ACS Chemical Biology},
volume = {9},
number = {3},
pages = {613-616},
note = {Ad7wi Times Cited:0 Cited References
Count:32},
abstract = {The substitution of alpha-amino acids by
homologated amino acids has a strong
impact on the overall structure and
topology of peptides, usually leading to a
loss in thermal stability. Here, we report
on the identification of an ideal core
packing between an alpha-helical peptide
and an alpha beta gamma-chimera via phage
display. Selected peptides assemble with
the chimeric sequence with thermal
stabilities that are comparable to that of
the parent bundle consisting purely of
alpha-amino acids. With the help of MD
simulations and mutational analysis this
stability could be explained by the
formation of an interhelical H-bond
between the selected cysteine and a
backbone carbonyl of the
beta/gamma-segment. Gained results can be
directly applied in the design of
biologically relevant peptides containing
beta- and gamma-amino acids.},
keywords = {phage display amino-acids foldamers
proteins conformations backbone residues
insights mimicry design},
ISSN = {1554-8929},
DOI = {10.1021/Cb4007979},
url = {Go to ISI://WOS:000333477300005
http://pubs.acs.org/doi/pdfplus/10.1021/cb4007979},
year = {2014},
type = {Journal Article}
}
x
An unusual interstrand h-bond stabilizes the heteroassembly of helical alpha beta gamma-chimeras with natural peptides
The substitution of alpha-amino acids by homologated amino acids has a strong impact on the overall structure and topology of peptides, usually leading to a loss in thermal stability. Here, we report on the identification of an ideal core packing between an alpha-helical peptide and an alpha beta gamma-chimera via phage display. Selected peptides assemble with the chimeric sequence with thermal stabilities that are comparable to that of the parent bundle consisting purely of alpha-amino acids. With the help of MD simulations and mutational analysis this stability could be explained by the formation of an interhelical H-bond between the selected cysteine and a backbone carbonyl of the beta/gamma-segment. Gained results can be directly applied in the design of biologically relevant peptides containing beta- and gamma-amino acids.
E. K. Nyakatura, J. Mortier, V. S. Radtke, S. Wieczorek, R. Rezaei Araghi, C. Baldauf, G. Wolber, and B. Koksch. β- and γ-amino acids at α-helical interfaces: Toward the formation of highly stable foldameric coiled coils, ACS Medicinal Chemistry Letters, 5(12):1300-1303, 2014.
Links:
[doi:10.1021/ml500361c]
[show BibTeX]
[show abstract]
x
@article{RN154,
author = {Nyakatura, Elisabeth K. and Mortier,
Jérémie and Radtke, Vanessa S. and
Wieczorek, Sebastian and Rezaei Araghi,
Raheleh and Baldauf, Carsten and Wolber,
Gerhard and Koksch, Beate},
title = {β- and γ-amino acids at α-helical
interfaces: Toward the formation of highly
stable foldameric coiled coils},
journal = {ACS Medicinal Chemistry Letters},
volume = {5},
number = {12},
pages = {1300-1303},
abstract = {Since peptides are vital for cellular and
pathogenic processes, much effort has been
put into the design of unnatural oligomers
that mimic natural peptide structures,
also referred to as foldamers. However, to
enable the specific application of
foldamers, a thorough characterization of
their interaction profiles in native
protein environments is required. We
report here the application of phage
display for the identification of suitable
helical environments for a sequence
comprising an alternating set of ?- and
?-amino acids. In vitro selected sequences
show that an increase in the hydrophobic
surface area at the helical interface as
well as the incorporation of a polar
H-bond donor functionality can
significantly improve interhelical
interactions involving backbone-extended
amino acids. Thus, our data provide
insight into the principles of the
rational design of foldameric inhibitors
for protein?protein interactions.},
DOI = {10.1021/ml500361c},
url = {http://dx.doi.org/10.1021/ml500361c
http://pubs.acs.org/doi/pdfplus/10.1021/ml500361c},
year = {2014},
type = {Journal Article}
}
x
β- and γ-amino acids at α-helical interfaces: Toward the formation of highly stable foldameric coiled coils
Since peptides are vital for cellular and pathogenic processes, much effort has been put into the design of unnatural oligomers that mimic natural peptide structures, also referred to as foldamers. However, to enable the specific application of foldamers, a thorough characterization of their interaction profiles in native protein environments is required. We report here the application of phage display for the identification of suitable helical environments for a sequence comprising an alternating set of ?- and ?-amino acids. In vitro selected sequences show that an increase in the hydrophobic surface area at the helical interface as well as the incorporation of a polar H-bond donor functionality can significantly improve interhelical interactions involving backbone-extended amino acids. Thus, our data provide insight into the principles of the rational design of foldameric inhibitors for protein?protein interactions.
R. Ottana, R. Maccari, J. Mortier, A. Caselli, S. Amuso, G. Camici, A. Rotondo, G. Wolber, and P. Paoli. Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells, Eur J Med Chem, 71:112-127, 2014.
Links:
[doi:10.1016/J.Ejmech.2013.11.001]
[show BibTeX]
[show abstract]
x
@article{RN9,
author = {Ottana, R. and Maccari, R. and Mortier,
J. and Caselli, A. and Amuso, S. and
Camici, G. and Rotondo, A. and Wolber, G.
and Paoli, P.},
title = {Synthesis, biological activity and
structure-activity relationships of new
benzoic acid-based protein tyrosine
phosphatase inhibitors endowed with
insulinomimetic effects in mouse C2C12
skeletal muscle cells},
journal = {European Journal of Medicinal Chemistry},
volume = {71},
pages = {112-127},
note = {Ab0qb Times Cited:0 Cited References
Count:70},
abstract = {Insulin resistance is a complex altered
metabolic condition characterized by
impaired insulin signaling and implicated
in the pathogenesis of serious human
diseases, such as diabetes, obesity,
neurodegenerative pathologies. In pursuing
our aim to identify new agents able to
improve cellular insulin sensitivity, we
have synthesized new
4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]
benzoic acids (5, 8) and evaluated their
inhibitory activity towards human protein
tyrosine phosphatases PTP1B, LMW-PTP and
TCPTP, enzymes which are involved in the
development of insulin resistance.
Compounds 5 and 8 showed from moderate to
significant selectivity toward PTP1B over
both the highly homologous TCPTP and the
two isoforms of human LMW-PTP. In
addition, most of the tested compounds
selectively inhibited LMW-PTP IF1 over the
isoform IF2. Docking studies into the
active sites of PTP1B and LMW-PTP aided
the rationalization of the observed PTP
inhibitory profile. Moreover, most tested
compounds were capable to induce the
insulin metabolic pathway in mouse C2C12
skeletal muscle cells by remarkably
stimulating both IR beta phosphorylation
and 2-deoxyglucose cellular uptake. (C)
2013 Elsevier Masson SAS. All rights
reserved.},
keywords = {protein tyrosine phosphatases enzyme
inhibitors insulinomimetic effects
molecular docking
5-arylidene-4-thiazolidinone derivatives
4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3yl)methyl]benzoic
acids weight phosphotyrosyl phosphatase
increased insulin sensitivity
structure-based optimization
cardiovascular-disease signal-transduction
alzheimers-disease metabolic syndrome
diabetes-mellitus leptin resistance
crystal-structure},
ISSN = {0223-5234},
DOI = {10.1016/J.Ejmech.2013.11.001},
url = {Go to ISI://WOS:000331496100013
http://ac.els-cdn.com/S0223523413007319/1-s2.0-S0223523413007319-main.pdf?_tid= 9b3132fc-4240-11e4-974e-00000aacb361&acdnat=1411380777_e8fb8750bd8d2cbe6a8717d6177ecfcd},
year = {2014},
type = {Journal Article}
}
x
Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells
Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl] benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested compounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IR beta phosphorylation and 2-deoxyglucose cellular uptake. (C) 2013 Elsevier Masson SAS. All rights reserved.
A. Perdih, M. Hrast, H. Barreteau, S. Gobec, G. Wolber, and T. Solmajer. Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF), Bioorg Med Chem, 22(15):4124-4134, 2014.
Links:
[doi:10.1016/j.bmc.2014.05.058]
[show BibTeX]
[show abstract]
x
@article{RN131,
author = {Perdih, Andrej and Hrast, Martina and
Barreteau, Hélène and Gobec, Stanislav
and Wolber, Gerhard and Solmajer, Tom},
title = {Benzene-1,3-dicarboxylic acid
2,5-dimethylpyrrole derivatives as
multiple inhibitors of bacterial Mur
ligases (MurC-MurF)},
journal = {Bioorganic & Medicinal Chemistry},
volume = {22},
number = {15},
pages = {4124-4134},
abstract = {Enzymes catalyzing the biosynthesis of
bacterial peptidoglycan represent
traditionally a collection of highly
selective targets for novel antibacterial
drug design. Four members of the bacterial
Mur ligase family—MurC, MurD, MurE and
MurF—are involved in the intracellular
steps of peptidoglycan biosynthesis,
catalyzing the synthesis of the peptide
moiety of the Park’s nucleotide. In our
previous virtual screening campaign, a
chemical class of benzene-1,3-dicarboxylic
acid 2,5-dimethylpyrrole derivatives
exhibiting dual MurD/MurE inhibition
properties was discovered. In the present
study we further investigated this class
of compounds by performing inhibition
assays on all four Mur ligases
(MurC–MurF). Furthermore, molecular
dynamics (MD) simulation studies of one of
the initially discovered compound 1 were
performed to explore its geometry as well
as its energetic behavior based on the
Linear Interaction Energy (LIE) method.
Further in silico virtual screening (VS)
experiments based on the parent active
compound 1 were conducted to optimize the
discovered series. Selected hits were
assayed against all Escherichia coli
MurC–MurF enzymes in biochemical
inhibition assays and molecules 10–14
containing benzene-1,3-dicarboxylic acid
2,5-dimethylpyrrole coupled with five
member-ring rhodanine moiety were found to
be multiple inhibitors of the whole
MurC–MurF cascade of bacterial enzymes
in the micromolar range. Steady-state
kinetics studies suggested this class to
act as competitive inhibitors of the MurD
enzyme towards d-Glu. These compounds
represent novel valuable starting point in
the development of novel antibacterial
agents.},
keywords = {Bacterial Mur (MurC–MurF) ligase
Structure-based pharmacophores Virtual
screening Molecular docking Molecular
dynamics (MD) Linear Interaction Energy
(LIE) method Antibacterial agents Drug
design},
ISSN = {0968-0896},
DOI = {10.1016/j.bmc.2014.05.058},
url = {http://www.sciencedirect.com/science/article/pii/S0968089614004179
http://ac.els-cdn.com/S0968089614004179/1-s2.0-S0968089614004179-main.pdf?_tid= 97a047d6-4240-11e4-8cc9-00000aacb35e&acdnat=1411380771_9a11a24bf370dd0c42a4252548df3aaa},
year = {2014},
type = {Journal Article}
}
x
Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF)
Enzymes catalyzing the biosynthesis of bacterial peptidoglycan represent traditionally a collection of highly selective targets for novel antibacterial drug design. Four members of the bacterial Mur ligase family—MurC, MurD, MurE and MurF—are involved in the intracellular steps of peptidoglycan biosynthesis, catalyzing the synthesis of the peptide moiety of the Park’s nucleotide. In our previous virtual screening campaign, a chemical class of benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives exhibiting dual MurD/MurE inhibition properties was discovered. In the present study we further investigated this class of compounds by performing inhibition assays on all four Mur ligases (MurC–MurF). Furthermore, molecular dynamics (MD) simulation studies of one of the initially discovered compound 1 were performed to explore its geometry as well as its energetic behavior based on the Linear Interaction Energy (LIE) method. Further in silico virtual screening (VS) experiments based on the parent active compound 1 were conducted to optimize the discovered series. Selected hits were assayed against all Escherichia coli MurC–MurF enzymes in biochemical inhibition assays and molecules 10–14 containing benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole coupled with five member-ring rhodanine moiety were found to be multiple inhibitors of the whole MurC–MurF cascade of bacterial enzymes in the micromolar range. Steady-state kinetics studies suggested this class to act as competitive inhibitors of the MurD enzyme towards d-Glu. These compounds represent novel valuable starting point in the development of novel antibacterial agents.
A. Perdih, M. Hrast, H. Barreteau, S. Gobec, G. Wolber, and T. Solmajer. Inhibitor Design Strategy Based on an Enzyme Structural Flexibility: A Case of Bacterial MurD Ligase, J Chem Inf Model, 54(5):1451-1466, 2014.
Links:
[doi:10.1021/Ci500104m]
[show BibTeX]
[show abstract]
x
@article{RN2,
author = {Perdih, A. and Hrast, M. and Barreteau,
H. and Gobec, S. and Wolber, G. and
Solmajer, T.},
title = {Inhibitor Design Strategy Based on an
Enzyme Structural Flexibility: A Case of
Bacterial MurD Ligase},
journal = {Journal of Chemical Information and
Modeling},
volume = {54},
number = {5},
pages = {1451-1466},
note = {Ai1tj Times Cited:0 Cited References
Count:51},
abstract = {Increasing bacterial resistance to
available antibiotics stimulated the
discovery of novel efficacious
antibacterial agents. The biosynthesis of
the bacterial peptidoglycan, where the
MurD enzyme is involved in the
intracellular phase of the
UDP-MurNAc-pentapeptide formation,
represents a collection of highly
selective targets for novel antibacterial
drug design. In our previous computational
studies, the C-terminal domain motion of
the MurD ligase was investigated using
Targeted Molecular Dynamic (TMD)
simulation and the Off-Path Simulation
(OPS) technique. In this study, we present
a drug design strategy using multiple
protein structures for the identification
of novel MurD ligase inhibitors. Our main
focus was the ATP-binding site of the MurD
enzyme. In the first stage, three MurD
protein conformations were selected based
on the obtained OPS/TMD data as the
initial criterion. Subsequently, a
two-stage virtual screening approach was
utilized combining derived structure-based
pharmacophores with molecular docking
calculations. Selected compounds were then
assayed in the established enzyme binding
assays, and compound 3 from the
aminothiazole class was discovered to act
as a dual MurC/MurD inhibitor in the
micomolar range. A steady-state kinetic
study was performed on the MurD enzyme to
provide further information about the
mechanistic aspects of its inhibition. In
the final stage, all used conformations of
the MurD enzyme with compound 3 were
simulated in classical molecular dynamics
(MD) simulations providing atomistic
insights of the experimental results.
Overall, the study depicts several
challenges that need to be addressed when
trying to hit a flexible moving target
such as the presently studied bacterial
MurD enzyme and show the possibilities of
how computational tools can be
proficiently used at all stages of the
drug discovery process.},
keywords = {molecular-dynamics simulation
escherichia-coli peptidoglycan
biosynthesis protein flexibility drug
discovery kinetic mechanism hiv-1 protease
adding enzyme force-fields cell-wall},
ISSN = {1549-9596},
DOI = {10.1021/Ci500104m},
url = {Go to ISI://WOS:000336637400016
http://pubs.acs.org/doi/pdfplus/10.1021/ci500104m},
year = {2014},
type = {Journal Article}
}
x
Inhibitor Design Strategy Based on an Enzyme Structural Flexibility: A Case of Bacterial MurD Ligase
Increasing bacterial resistance to available antibiotics stimulated the discovery of novel efficacious antibacterial agents. The biosynthesis of the bacterial peptidoglycan, where the MurD enzyme is involved in the intracellular phase of the UDP-MurNAc-pentapeptide formation, represents a collection of highly selective targets for novel antibacterial drug design. In our previous computational studies, the C-terminal domain motion of the MurD ligase was investigated using Targeted Molecular Dynamic (TMD) simulation and the Off-Path Simulation (OPS) technique. In this study, we present a drug design strategy using multiple protein structures for the identification of novel MurD ligase inhibitors. Our main focus was the ATP-binding site of the MurD enzyme. In the first stage, three MurD protein conformations were selected based on the obtained OPS/TMD data as the initial criterion. Subsequently, a two-stage virtual screening approach was utilized combining derived structure-based pharmacophores with molecular docking calculations. Selected compounds were then assayed in the established enzyme binding assays, and compound 3 from the aminothiazole class was discovered to act as a dual MurC/MurD inhibitor in the micomolar range. A steady-state kinetic study was performed on the MurD enzyme to provide further information about the mechanistic aspects of its inhibition. In the final stage, all used conformations of the MurD enzyme with compound 3 were simulated in classical molecular dynamics (MD) simulations providing atomistic insights of the experimental results. Overall, the study depicts several challenges that need to be addressed when trying to hit a flexible moving target such as the presently studied bacterial MurD enzyme and show the possibilities of how computational tools can be proficiently used at all stages of the drug discovery process.
C. Rakers, S. Schwerdtfeger, J. Mortier, S. Duwe, T. Wolff, G. Wolber, and M. F. Melzig. Inhibitory potency of flavonoid derivatives on influenza virus neuraminidase, Bioorg Med Chem Lett, 24(17):4312-4317, 2014.
Links:
[doi:10.1016/j.bmcl.2014.07.010]
[show BibTeX]
[show abstract]
x
@article{RN130,
author = {Rakers, Christin and Schwerdtfeger,
Sverre-Morten and Mortier, Jérémie and
Duwe, Susanne and Wolff, Thorsten and
Wolber, Gerhard and Melzig, Matthias F.},
title = {Inhibitory potency of flavonoid
derivatives on influenza virus
neuraminidase},
journal = {Bioorganic & Medicinal Chemistry
Letters},
volume = {24},
number = {17},
pages = {4312-4317},
abstract = {The constant risk of emerging new
influenza virus strains that are resistant
to established inhibitors like oseltamivir
leaves influenza neuraminidase (NA) a
prominent target for drug design. The
inhibitory activity of several flavonoid
derivatives was experimentally tested in
comparison to oseltamivir for the NA
expressed by the seasonal influenza virus
strains A/California/7/09 (A(H1N1)pdm09),
A/Perth/16/09 (A(H3N2)), and
B/Brisbane/60/08. IC50 values of
polyphenols confirmed moderate inhibition
in the μM range. Structurally, the amount
and site of glycosylation of tested
flavonoids have no significant influence
on their inhibitory potency. In a
pharmacophore-based docking approach the
structure–activity relationship was
evaluated. Molecular dynamics simulations
revealed highly flexible parts of the
enzyme and the contribution of salt
bridges to the structural stability of NA.
The findings of this study elucidate the
impact of flavonoids on viral
neuraminidase activity and the analysis of
their modes of action provide valuable
information about the mechanism of NA
inhibition.},
keywords = {Influenza Neuraminidase Flavonoids
Molecular dynamics Docking},
ISSN = {0960-894X},
DOI = {10.1016/j.bmcl.2014.07.010},
url = {http://www.sciencedirect.com/science/article/pii/S0960894X14007343
http://ac.els-cdn.com/S0960894X14007343/1-s2.0-S0960894X14007343-main.pdf?_tid= 9244019c-4240-11e4-af5e-00000aab0f27&acdnat=1411380762_b399fa4d56fe704fa20d99c706fd5f57},
year = {2014},
type = {Journal Article}
}
x
Inhibitory potency of flavonoid derivatives on influenza virus neuraminidase
The constant risk of emerging new influenza virus strains that are resistant to established inhibitors like oseltamivir leaves influenza neuraminidase (NA) a prominent target for drug design. The inhibitory activity of several flavonoid derivatives was experimentally tested in comparison to oseltamivir for the NA expressed by the seasonal influenza virus strains A/California/7/09 (A(H1N1)pdm09), A/Perth/16/09 (A(H3N2)), and B/Brisbane/60/08. IC50 values of polyphenols confirmed moderate inhibition in the μM range. Structurally, the amount and site of glycosylation of tested flavonoids have no significant influence on their inhibitory potency. In a pharmacophore-based docking approach the structure–activity relationship was evaluated. Molecular dynamics simulations revealed highly flexible parts of the enzyme and the contribution of salt bridges to the structural stability of NA. The findings of this study elucidate the impact of flavonoids on viral neuraminidase activity and the analysis of their modes of action provide valuable information about the mechanism of NA inhibition.
J. Schmitz, D. van der Mey, M. Bermudez, J. Klöckner, R. Schrage, E. Kostenis, C. Tränkle, G. Wolber, K. Mohr, and U. Holzgrabe. Dualsteric muscarinic antagonists - orthosteric binding pose controls allosteric subtype selectivity, J Med Chem, 57(15):6739-6750, 2014.
Links:
[doi:10.1021/jm500790x]
[show BibTeX]
[show abstract]
x
@article{RN129,
author = {Schmitz, Jens and van der Mey, Dorina and
Bermudez, Marcel and Klöckner, Jessica
and Schrage, Ramona and Kostenis, Evi and
Tränkle, Christian and Wolber, Gerhard
and Mohr, Klaus and Holzgrabe, Ulrike},
title = {Dualsteric muscarinic antagonists -
orthosteric binding pose controls
allosteric subtype selectivity},
journal = {Journal of Medicinal Chemistry},
volume = {57},
number = {15},
pages = {6739-6750},
abstract = {Bivalent ligands of G protein-coupled
receptors have been shown to
simultaneously either bind to two adjacent
receptors or to bridge different parts of
one receptor protein. Recently, we found
that bivalent agonists of muscarinic
receptors can simultaneously occupy both
the orthosteric transmitter binding site
and the allosteric vestibule of the
receptor protein. Such dualsteric agonists
display a certain extent of subtype
selectivity, generate pathway-specific
signaling, and in addition may allow for
designed partial agonism. Here, we want to
extend the concept to bivalent antagonism.
Using the phthal- and naphthalimide
moieties, which bind to the allosteric,
extracellular site, and atropine or
scopolamine as orthosteric building
blocks, both connected by a hexamethonium
linker, we were able to prove a bitopic
binding mode of antagonist hybrids for the
first time. This is demonstrated by
structure–activity relationships,
site-directed mutagenesis, molecular
docking studies, and molecular dynamics
simulations. Findings revealed that a
difference in spatial orientation of the
orthosteric tropane moiety translates into
a divergent M2/M5 subtype selectivity of
the corresponding bitopic hybrids.},
keywords = {gpcr},
ISSN = {0022-2623},
DOI = {10.1021/jm500790x},
url = {http://pubs.acs.org/doi/pdfplus/10.1021/jm500790x},
year = {2014},
type = {Journal Article}
}
x
Dualsteric muscarinic antagonists - orthosteric binding pose controls allosteric subtype selectivity
Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal- and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure–activity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.
M. A. Seiter, S. Salcher, M. Rupp, J. Hagenbuchner, U. Kiechl-Kohlendorfer, J. Mortier, G. Wolber, J. M. Rollinger, P. Obexer, and M. J. Ausserlechner. Discovery of Sanggenon G as a natural cell-permeable small-molecular weight inhibitor of X-linked inhibitor of apoptosis protein (XIAP), FEBS Open Bio, 4:659-671, 2014.
Links:
[doi:10.1016/j.fob.2014.07.001]
[show BibTeX]
[show abstract]
x
@article{RN132,
author = {Seiter, Maximilian A. and Salcher, Stefan
and Rupp, Martina and Hagenbuchner, Judith
and Kiechl-Kohlendorfer, Ursula and
Mortier, Jérémie and Wolber, Gerhard and
Rollinger, Judith M. and Obexer, Petra and
Ausserlechner, Michael J.},
title = {Discovery of Sanggenon G as a natural
cell-permeable small-molecular weight
inhibitor of X-linked inhibitor of
apoptosis protein (XIAP)},
journal = {FEBS Open Bio},
volume = {4},
number = {0},
pages = {659-671},
abstract = {Defects in the regulation of apoptosis
are one main cause of cancer development
and may result from overexpression of
anti-apoptotic proteins such as the
X-linked inhibitor of apoptosis protein
(XIAP). XIAP is frequently overexpressed
in human leukemia and prostate and breast
tumors. Inhibition of apoptosis by XIAP is
mainly coordinated through direct binding
to the initiator caspase-9 via its
baculovirus-IAP-repeat-3 (BIR3) domain.
XIAP inhibits caspases directly making it
to an attractive target for anti-cancer
therapy. In the search for novel,
non-peptidic XIAP inhibitors in this study
we focused on the chemical constituents of
sāng bái pí (mulberry root bark). Most
promising candidates of this plant were
tested biochemically in vitro by a
fluorescence polarization (FP) assay and
in vivo via protein fragment
complementation analysis (PCA). We
identified the Diels Alder adduct
Sanggenon G (SG1) as a novel,
small-molecular weight inhibitor of XIAP.
As shown by FP and PCA analyses, SG1 binds
specifically to the BIR3 domain of XIAP
with a binding affinity of 34.26 μM.
Treatment of the transgenic leukemia cell
line Molt3/XIAP with SG1 enhances
caspase-8, -3 and -9 cleavage, displaces
caspase-9 from XIAP as determined by
immunoprecipitation experiments and
sensitizes these cells to
etoposide-induced apoptosis. SG1 not only
sensitizes the XIAP-overexpressing
leukemia cell line Molt3/XIAP to etoposide
treatment but also different neuroblastoma
cell lines endogenously expressing high
XIAP levels. Taken together, Sanggenon G
(SG1) is a novel, natural, non-peptidic,
small-molecular inhibitor of XIAP that can
serve as a starting point to develop a new
class of improved XIAP inhibitors.},
keywords = {application sbdd},
ISSN = {2211-5463},
DOI = {10.1016/j.fob.2014.07.001},
url = {http://www.sciencedirect.com/science/article/pii/S2211546314000655
http://ac.els-cdn.com/S2211546314000655/1-s2.0-S2211546314000655-main.pdf?_tid= 8f475c96-4240-11e4-ad09-00000aacb360&acdnat=1411380757_e7c5cf33054a97e0fc81b36bee35993e},
year = {2014},
type = {Journal Article}
}
x
Discovery of Sanggenon G as a natural cell-permeable small-molecular weight inhibitor of X-linked inhibitor of apoptosis protein (XIAP)
Defects in the regulation of apoptosis are one main cause of cancer development and may result from overexpression of anti-apoptotic proteins such as the X-linked inhibitor of apoptosis protein (XIAP). XIAP is frequently overexpressed in human leukemia and prostate and breast tumors. Inhibition of apoptosis by XIAP is mainly coordinated through direct binding to the initiator caspase-9 via its baculovirus-IAP-repeat-3 (BIR3) domain. XIAP inhibits caspases directly making it to an attractive target for anti-cancer therapy. In the search for novel, non-peptidic XIAP inhibitors in this study we focused on the chemical constituents of sāng bái pí (mulberry root bark). Most promising candidates of this plant were tested biochemically in vitro by a fluorescence polarization (FP) assay and in vivo via protein fragment complementation analysis (PCA). We identified the Diels Alder adduct Sanggenon G (SG1) as a novel, small-molecular weight inhibitor of XIAP. As shown by FP and PCA analyses, SG1 binds specifically to the BIR3 domain of XIAP with a binding affinity of 34.26 μM. Treatment of the transgenic leukemia cell line Molt3/XIAP with SG1 enhances caspase-8, -3 and -9 cleavage, displaces caspase-9 from XIAP as determined by immunoprecipitation experiments and sensitizes these cells to etoposide-induced apoptosis. SG1 not only sensitizes the XIAP-overexpressing leukemia cell line Molt3/XIAP to etoposide treatment but also different neuroblastoma cell lines endogenously expressing high XIAP levels. Taken together, Sanggenon G (SG1) is a novel, natural, non-peptidic, small-molecular inhibitor of XIAP that can serve as a starting point to develop a new class of improved XIAP inhibitors.
A. Temirak, Y. M. Shaker, F. A. F. Ragab, M. M. Ali, S. M. Soliman, J. Mortier, G. Wolber, H. I. Ali, and H. I. El Diwani. Synthesis, biological evaluation, and docking studies of new 2-furylbenzimidazoles as anti- angiogenic agents: Part II, Arch Pharm, 347(4):291-304, 2014.
Links:
[doi:10.1002/Ardp.201300356]
[show BibTeX]
[show abstract]
x
@article{RN4,
author = {Temirak, A. and Shaker, Y. M. and Ragab,
F. A. F. and Ali, M. M. and Soliman, S. M.
and Mortier, J. and Wolber, G. and Ali, H.
I. and El Diwani, H. I.},
title = {Synthesis, biological evaluation, and
docking studies of new
2-furylbenzimidazoles as anti- angiogenic
agents: Part II},
journal = {Archiv der Pharmazie},
volume = {347},
number = {4},
pages = {291-304},
note = {Ae0wj Times Cited:0 Cited References
Count:38},
abstract = {The 2-(5-methyl-2-furyl)-1H-benzimidazole
moiety has shown promising activity
against vascular endothelial growth factor
(VEGF)-induced angiogenesis. In part I of
this study, we have synthesized new
analogs and tested their anti-angiogenic
potentials. Here, we continue our previous
study with different new analogs. Some
compounds show promising cytotoxic
activity against the human breast cancer
cell line MCF-7, with IC50 in the range of
7.80-13.90 mu g/mL, and exhibited
remarkable in vitro inhibition against
VEGF in the MCF-7 cancer cell line, with
95-98% of inhibition in comparison to
tamoxifen as reference (IC50: 8.00 mu
g/mL, % of inhibition=98%). Additionally,
a molecular docking study was carried out
to gain insight into plausible binding
modes and to understand the
structure-activity relationships of the
synthesized compounds.},
keywords = {application},
ISSN = {0365-6233},
DOI = {10.1002/Ardp.201300356},
url = {Go to ISI://WOS:000333686700008
http://onlinelibrary.wiley.com/store/10.1002/ardp.201300356/asset/ardp201300356.pdf?v= 1&t=i0dnk0o7&s=adf05599c316cb9a97e07a9131eb4f64f613102a},
year = {2014},
type = {Journal Article}
}
x
Synthesis, biological evaluation, and docking studies of new 2-furylbenzimidazoles as anti- angiogenic agents: Part II
The 2-(5-methyl-2-furyl)-1H-benzimidazole moiety has shown promising activity against vascular endothelial growth factor (VEGF)-induced angiogenesis. In part I of this study, we have synthesized new analogs and tested their anti-angiogenic potentials. Here, we continue our previous study with different new analogs. Some compounds show promising cytotoxic activity against the human breast cancer cell line MCF-7, with IC50 in the range of 7.80-13.90 mu g/mL, and exhibited remarkable in vitro inhibition against VEGF in the MCF-7 cancer cell line, with 95-98% of inhibition in comparison to tamoxifen as reference (IC50: 8.00 mu g/mL, % of inhibition=98%). Additionally, a molecular docking study was carried out to gain insight into plausible binding modes and to understand the structure-activity relationships of the synthesized compounds.
C. D. Cadicamo, J. Mortier, G. Wolber, M. Hell, I. E. Heinrich, D. Michel, L. Semlin, U. Berger, H. C. Korting, H. D. Holtje, B. Koksch, and C. Borelli. Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans, Biochem Pharmacol, 85(7):881-887, 2013.
Links:
[doi:10.1016/J.Bcp.2012.12.008]
[show BibTeX]
[show abstract]
x
@article{RN19,
author = {Cadicamo, C. D. and Mortier, J. and
Wolber, G. and Hell, M. and Heinrich, I.
E. and Michel, D. and Semlin, L. and
Berger, U. and Korting, H. C. and Holtje,
H. D. and Koksch, B. and Borelli, C.},
title = {Design, synthesis, inhibition studies,
and molecular modeling of pepstatin
analogues addressing different secreted
aspartic proteinases of Candida albicans},
journal = {Biochemical Pharmacology},
volume = {85},
number = {7},
pages = {881-887},
note = {110DO Times Cited:1 Cited References
Count:39},
abstract = {The family of secreted aspartic
proteinases is known as an important
virulence factor of yeast infections by
Candida albicans in particular, which is
the most common fungal pathogen for humans
with respect to systemic disease. Due to
the continuing increase of drug resistant
strains, these proteinases are currently
considered as promising drug target
candidates. Based on the known
Sap2-substrate specificity data and X-ray
analyses of Sap/inhibitor complexes, three
libraries of inhibitors were designed and
synthesized by modifying the structure of
pepstatin A, a common non-selective
aspartic proteinase inhibitor, at the P3,
P2, or P2' position. These novel
inhibitors showed high inhibitory
potencies for the isoenzymes Sap1, Sap3,
Sap5 and Sap6. Then, the affinity and
selectivity of the peptide ligands were
investigated by molecular modeling,
highlighting new key structural
information for the design of potent and
selective anti-virulence agents targeting
Candida albicans. (c) 2012 Elsevier Inc.
All rights reserved.},
keywords = {anti-virulence agent peptidomimetic
candidapeptidase secreted aspartic
proteinases inhibition pepstatin candida
albicans solid-phase synthesis
crystal-structure in-vivo virulence
expression proteases pharmacophores
parapsilosis pathogenesis repository},
ISSN = {0006-2952},
DOI = {10.1016/J.Bcp.2012.12.008},
url = {Go to ISI://WOS:000316423000004
http://ac.els-cdn.com/S0006295212007940/1-s2.0-S0006295212007940-main.pdf?_tid= b5706d5e-4240-11e4-87eb-00000aab0f27&acdnat=1411380821_0911f281fa7759a5300962e9ca09acb7},
year = {2013},
type = {Journal Article}
}
x
Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans
The family of secreted aspartic proteinases is known as an important virulence factor of yeast infections by Candida albicans in particular, which is the most common fungal pathogen for humans with respect to systemic disease. Due to the continuing increase of drug resistant strains, these proteinases are currently considered as promising drug target candidates. Based on the known Sap2-substrate specificity data and X-ray analyses of Sap/inhibitor complexes, three libraries of inhibitors were designed and synthesized by modifying the structure of pepstatin A, a common non-selective aspartic proteinase inhibitor, at the P3, P2, or P2' position. These novel inhibitors showed high inhibitory potencies for the isoenzymes Sap1, Sap3, Sap5 and Sap6. Then, the affinity and selectivity of the peptide ligands were investigated by molecular modeling, highlighting new key structural information for the design of potent and selective anti-virulence agents targeting Candida albicans. (c) 2012 Elsevier Inc. All rights reserved.
K. N. de Oliveira, V. Andermark, S. von Grafenstein, L. A. Onambele, G. Dahl, R. Rubbiani, G. Wolber, C. Gabbiani, L. Messori, A. Prokop, and I. Ott. Butyltin(IV) benzoates: Inhibition of thioredoxin reductase, tumor cell growth inhibition, and interactions with proteins, ChemMedChem, 8(2):256-264, 2013.
Links:
[doi:10.1002/Cmdc.201200505]
[show BibTeX]
[show abstract]
x
@article{RN20,
author = {de Oliveira, K. N. and Andermark, V. and
von Grafenstein, S. and Onambele, L. A.
and Dahl, G. and Rubbiani, R. and Wolber,
G. and Gabbiani, C. and Messori, L. and
Prokop, A. and Ott, I.},
title = {Butyltin(IV) benzoates: Inhibition of
thioredoxin reductase, tumor cell growth
inhibition, and interactions with
proteins},
journal = {Chemmedchem},
volume = {8},
number = {2},
pages = {256-264},
note = {079LU Times Cited:3 Cited References
Count:59},
abstract = {Thioredoxin reductase (TrxR) is
overexpressed in cancer cells and is
therefore a putative cancer target.
Inhibition of this enzyme is considered an
important strategy for the development of
new chemotherapeutic agents with a
specific mechanism of action. Organotin
compounds have been described as
experimental antitumor agents, yet their
mechanism of action remains largely
unknown. Based on the outcome of a virtual
screening study, various di- and
tri-n-butyltin(IV) carboxylates were
synthesized, and their biological
properties were evaluated. All synthesized
compounds were able to inhibit TrxR
selectively within the micromolar range
and showed potent antitumor activity
against HT-29 and MCF-7 cancer cell lines.
Moreover, tin(IV) organometallics were
found to strongly induce apoptosis in the
BJAB lymphoma cell line. Mass spectrometry
and atomic absorption spectroscopy
experiments revealed metal binding to
proteins, and efficient cellular uptake
was observed using a di-n-butyltin(IV)
complex as an example.},
keywords = {virtual screening antitumor agents
bioorganometallics thioredoxin reductases
tin gold(i) complexes cancer-therapy
organometallic compounds carboxylate
complexes organotin compounds
antitumor-activity metal-complexes tin
compound agents},
ISSN = {1860-7179},
DOI = {10.1002/Cmdc.201200505},
url = {Go to ISI://WOS:000314172700008
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200505/abstract
http://onlinelibrary.wiley.com/store/10.1002/cmdc.201200505/asset/256_ftp.pdf?v= 1&t=jdvll0lr&s=8cf79c478b87e51f4c1b5bb9748efa83ed85b36a},
year = {2013},
type = {Journal Article}
}
x
Butyltin(IV) benzoates: Inhibition of thioredoxin reductase, tumor cell growth inhibition, and interactions with proteins
Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di- and tri-n-butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT-29 and MCF-7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di-n-butyltin(IV) complex as an example.
M. Enthammer, E. S. Papadakis, M. S. Gachet, M. Deutsch, S. Schwaiger, K. Koziel, M. I. Ashraf, S. Khalid, G. Wolber, G. Packham, R. I. Cutress, H. Stuppner, and J. Troppmair. Isolation of a novel Thioflavin S-derived compound that inhibits BAG-1-mediated protein interactions and targets BRAF inhibitor-resistant cell lines, Mol Cancer Ther, 12(11):2400-2414, 2013.
Links:
[doi:10.1158/1535-7163.Mct-13-0142]
[show BibTeX]
[show abstract]
x
@article{RN12,
author = {Enthammer, M. and Papadakis, E. S. and
Gachet, M. S. and Deutsch, M. and
Schwaiger, S. and Koziel, K. and Ashraf,
M. I. and Khalid, S. and Wolber, G. and
Packham, G. and Cutress, R. I. and
Stuppner, H. and Troppmair, J.},
title = {Isolation of a novel Thioflavin S-derived
compound that inhibits BAG-1-mediated
protein interactions and targets BRAF
inhibitor-resistant cell lines},
journal = {Molecular Cancer Therapeutics},
volume = {12},
number = {11},
pages = {2400-2414},
note = {250WB Times Cited:0 Cited References
Count:62},
abstract = {Protein-protein interactions mediated
through the C-terminal Bcl-2-associated
athanogene (BAG) domain of BAG-1 are
critical for cell survival and
proliferation. Thioflavin S (NSC71948)-a
mixture of compounds resulting from the
methylation and sulfonation of primulin
base-has been shown to dose-dependently
inhibit the interaction between BAG-1 and
Hsc70 in vitro. In human breast cancer
cell lines, with high BAG-1 expression
levels, Thioflavin S reduces the binding
of BAG-1 to Hsc70, Hsp70, or CRAF and
decreases proliferation and viability.
Here, we report the development of a
protocol for the purification and
isolation of biologically active
constituents of Thioflavin S and the
characterization of the novel compound
Thio-2. Thio-2 blocked the growth of
several transformed cell lines, but had
much weaker effects on untransformed
cells. Thio-2 also inhibited the
proliferation of melanoma cell lines that
had become resistant to treatment with
PLX4032, an inhibitor of mutant BRAF. In
transformed cells, Thio-2 interfered with
intracellular signaling at the level of
RAF, but had no effect on the activation
of AKT. Thio-2 decreased binding of BAG-1
to Hsc70 and to a lesser extent BRAF in
vitro and in vivo, suggesting a possible
mechanism of action. Given that tumors
frequently develop resistance to kinase
inhibitors during treatment, Thio-2 and
related compounds may offer promising
alternative strategies to currently
available therapies. (C) 2013 AACR.},
keywords = {b-raf acquired-resistance thiazole dyes
human cancer melanoma kinase mutations
survival bag-1 activation},
ISSN = {1535-7163},
DOI = {10.1158/1535-7163.Mct-13-0142},
url = {Go to ISI://WOS:000326886000011
http://mct.aacrjournals.org/content/12/11/2400
http://mct.aacrjournals.org/content/12/11/2400.full.pdf},
year = {2013},
type = {Journal Article}
}
x
Isolation of a novel Thioflavin S-derived compound that inhibits BAG-1-mediated protein interactions and targets BRAF inhibitor-resistant cell lines
Protein-protein interactions mediated through the C-terminal Bcl-2-associated athanogene (BAG) domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948)-a mixture of compounds resulting from the methylation and sulfonation of primulin base-has been shown to dose-dependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70, or CRAF and decreases proliferation and viability. Here, we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines, but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells, Thio-2 interfered with intracellular signaling at the level of RAF, but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies. (C) 2013 AACR.
S. A. Galar, A. S. Abdelsamie, S. M. Soliman, J. Mortier, G. Wolber, M. M. Ali, H. Tokuda, N. Suzuki, A. Lida, R. A. Ramadan, and H. I. El Diwani. Design, synthesis and structure-activity relationship of novel quinoxaline derivatives as cancer chemopreventive agent by inhibition of tyrosine kinase receptor, Eur J Med Chem, 69:115-124, 2013.
Links:
[doi:10.1016/J.Ejmech.2013.07.049]
[show BibTeX]
[show abstract]
x
@article{RN13,
author = {Galar, S. A. and Abdelsamie, A. S. and
Soliman, S. M. and Mortier, J. and Wolber,
G. and Ali, M. M. and Tokuda, H. and
Suzuki, N. and Lida, A. and Ramadan, R. A.
and El Diwani, H. I.},
title = {Design, synthesis and structure-activity
relationship of novel quinoxaline
derivatives as cancer chemopreventive
agent by inhibition of tyrosine kinase
receptor},
journal = {European Journal of Medicinal Chemistry},
volume = {69},
pages = {115-124},
note = {302KR Times Cited:0 Cited References
Count:38},
abstract = {The cancer chemopreventive activity of
quinoxaline derivatives 1-20 has been
evaluated by studying the inhibitory
effect on Epstein-Barr virus early antigen
(EBV-EA) activation. The quinoxaline
derivatives 1-20 showed inhibitory effect
on EBV-EA activation without cytotoxicity
on Raji cells. All compounds exhibited
dose dependent inhibitory activities, most
of them showed significant activity at
1000 mol
ratio/12-O-tetradecanoylphorbol-13-acetate
(TPA). Compounds 7 and 9 exhibited
stronger inhibitory effects on the EBV-EA
activation than that of the representative
control, oleanolic acid, at the highest
measured concentration. In addition,
compounds 7-10 showed potent and selective
inhibition of human tyrosine kinase (TRK)
in liver cancer HepG2 and breast cancer
MCF-7 cell lines similar to the positive
control, doxorubicin. (C) 2013 Published
by Elsevier Masson SAS.},
keywords = {synthesis quinoxalines epstein-barr virus
cancer chemopreventive activity docking
protein tyrosine kinase antitumor-activity
protein-kinases ethyl
carboethoxyformimidate cells
phosphorylation hydrazine melanoma drug},
ISSN = {0223-5234},
DOI = {10.1016/J.Ejmech.2013.07.049},
url = {Go to ISI://WOS:000330603900011
http://ac.els-cdn.com/S0223523413005023/1-s2.0-S0223523413005023-main.pdf?_tid= ab4af826-4240-11e4-a1d8-00000aacb35d&acdnat=1411380804_70af19db3712904ba5a3c4ccdd1783ee},
year = {2013},
type = {Journal Article}
}
x
Design, synthesis and structure-activity relationship of novel quinoxaline derivatives as cancer chemopreventive agent by inhibition of tyrosine kinase receptor
The cancer chemopreventive activity of quinoxaline derivatives 1-20 has been evaluated by studying the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation. The quinoxaline derivatives 1-20 showed inhibitory effect on EBV-EA activation without cytotoxicity on Raji cells. All compounds exhibited dose dependent inhibitory activities, most of them showed significant activity at 1000 mol ratio/12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 7 and 9 exhibited stronger inhibitory effects on the EBV-EA activation than that of the representative control, oleanolic acid, at the highest measured concentration. In addition, compounds 7-10 showed potent and selective inhibition of human tyrosine kinase (TRK) in liver cancer HepG2 and breast cancer MCF-7 cell lines similar to the positive control, doxorubicin. (C) 2013 Published by Elsevier Masson SAS.
J. Leschner, G. Wennerberg, J. Feierler, M. Bermudez, B. Welte, I. Kalatskaya, G. Wolber, and A. Faussner. Interruption of the ionic lock in the Bradykinin B-2 receptor results in constitutive internalization and turns several antagonists into strong agonists, J Pharmacol Exp Ther, 344(1):85-95, 2013.
Links:
[doi:10.1124/Jpet.112.199190]
[show BibTeX]
[show abstract]
x
@article{RN21,
author = {Leschner, J. and Wennerberg, G. and
Feierler, J. and Bermudez, M. and Welte,
B. and Kalatskaya, I. and Wolber, G. and
Faussner, A.},
title = {Interruption of the ionic lock in the
Bradykinin B-2 receptor results in
constitutive internalization and turns
several antagonists into strong agonists},
journal = {Journal of Pharmacology and Experimental
Therapeutics},
volume = {344},
number = {1},
pages = {85-95},
note = {060VE Times Cited:3 Cited References
Count:47},
abstract = {The DRY motif with the highly conserved
R3.50 is a hallmark of family A G
protein-coupled receptors (GPCRs). The
crystal structure of rhodopsin revealed a
salt bridge between R135(3.50) and another
conserved residue, E247(6.30), in helix 6.
This ionic lock was shown to maintain
rhodopsin in its inactive state. Thus far,
little information is available on how
interruption of this ionic bond affects
signaling properties of nonrhodopsin
GPCRs, because the focus has been on
mutations of R3.50, although this residue
is indispensable for G protein activation.
To investigate the importance of an ionic
lock for overall receptor activity in a
nonrhodopsin GPCR, we mutated R128(3.50)
and E238(6.30) in the bradykinin (BK) B-2
receptor (B2R) and stably expressed the
constructs in HEK293 cells. As expected,
mutation of R3.50 resulted in lack of G
protein activation. In addition, this
mutation led to considerable constitutive
receptor internalization. Mutation of
E6.30 (mutants E6.30A and E6.30R) also
caused strong constitutive
internalization. Most intriguingly,
however, although the two E6.30 mutants
displayed no increased basal
phosphatidylinositol hydrolysis, they gave
a response to three different B2R
antagonists that was almost comparable to
that obtained with BK. In contrast,
swapping of R3.50 and E6.30, thus allowing
the formation of an inverse ionic bond,
resulted in rescue of the wild type
phenotype. These findings demonstrate for
the first time, to our knowledge, that
interruption of the ionic lock in a family
A GPCR can have distinctly different
effects on receptor internalization and G
protein stimulation, shedding new light on
its role in the activation process.},
keywords = {protein-coupled receptors
beta(2)-adrenergic receptor
phosphorylation sites crystal-structure
beta-arrestin ground-state dry motif
activation rhodopsin model gpcr},
ISSN = {0022-3565},
DOI = {10.1124/Jpet.112.199190},
url = {Go to ISI://WOS:000312805500011
http://jpet.aspetjournals.org/content/344/1/85.full.pdf},
year = {2013},
type = {Journal Article}
}
x
Interruption of the ionic lock in the Bradykinin B-2 receptor results in constitutive internalization and turns several antagonists into strong agonists
The DRY motif with the highly conserved R3.50 is a hallmark of family A G protein-coupled receptors (GPCRs). The crystal structure of rhodopsin revealed a salt bridge between R135(3.50) and another conserved residue, E247(6.30), in helix 6. This ionic lock was shown to maintain rhodopsin in its inactive state. Thus far, little information is available on how interruption of this ionic bond affects signaling properties of nonrhodopsin GPCRs, because the focus has been on mutations of R3.50, although this residue is indispensable for G protein activation. To investigate the importance of an ionic lock for overall receptor activity in a nonrhodopsin GPCR, we mutated R128(3.50) and E238(6.30) in the bradykinin (BK) B-2 receptor (B2R) and stably expressed the constructs in HEK293 cells. As expected, mutation of R3.50 resulted in lack of G protein activation. In addition, this mutation led to considerable constitutive receptor internalization. Mutation of E6.30 (mutants E6.30A and E6.30R) also caused strong constitutive internalization. Most intriguingly, however, although the two E6.30 mutants displayed no increased basal phosphatidylinositol hydrolysis, they gave a response to three different B2R antagonists that was almost comparable to that obtained with BK. In contrast, swapping of R3.50 and E6.30, thus allowing the formation of an inverse ionic bond, resulted in rescue of the wild type phenotype. These findings demonstrate for the first time, to our knowledge, that interruption of the ionic lock in a family A GPCR can have distinctly different effects on receptor internalization and G protein stimulation, shedding new light on its role in the activation process.
M. Levay, K. A. Krobert, K. Wittig, N. Voigt, M. Bermudez, G. Wolber, D. Dobrev, F. O. Levy, and T. Wieland. NSC23766, a widely used inhibitor of rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors, J Pharmacol Exp Ther, 347(1):69-79, 2013.
Links:
[doi:10.1124/Jpet.113.207266]
[show BibTeX]
[show abstract]
x
@article{RN14,
author = {Levay, M. and Krobert, K. A. and Wittig,
K. and Voigt, N. and Bermudez, M. and
Wolber, G. and Dobrev, D. and Levy, F. O.
and Wieland, T.},
title = {NSC23766, a widely used inhibitor of rac1
activation, additionally acts as a
competitive antagonist at muscarinic
acetylcholine receptors},
journal = {Journal of Pharmacology and Experimental
Therapeutics},
volume = {347},
number = {1},
pages = {69-79},
note = {220KX Times Cited:1 Cited References
Count:60},
abstract = {Small molecules interfering with Rac1
activation are considered as potential
drugs and are already studied in animal
models. A widely used inhibitor without
reported attenuation of RhoA activity is
NSC23766
[(N-6-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine
trihydrochloride]. We found that NSC23766
inhibits the M-2 muscarinic acetylcholine
receptor (M-2 mAChR)-induced Rac1
activation in neonatal rat cardiac
myocytes. Surprisingly, NSC27366
concomitantly suppressed the
carbachol-induced RhoA activation and a
M-2 mAChR-induced inotropic response in
isolated neonatal rat hearts requiring the
activation of Rho-dependent kinases. We
therefore aimed to identify the mechanisms
by which NSC23766 interferes with the
differentially mediated, M-2 mAChR-induced
responses. Interestingly, NSC23766 caused
a rightward shift of the carbachol
concentration response curve for the
positive inotropic response without
modifying carbachol efficacy. To analyze
the specificity of NSC23766, we compared
the carbachol and the similarly G(i)beta
gamma-mediated, adenosine-induced
activation of G(i) protein-regulated
potassium channel (GIRK) channels in human
atrial myocytes. Application of NSC23766
blocked the carbachol-induced K+ current
but had no effect on the adenosine-induced
GIRK current. Similarly, an adenosine A(1)
receptor-induced positive inotropic
response in neonatal rat hearts was not
attenuated by NSC23766. To investigate its
specificity toward the different mAChR
types, we studied the carbachol-induced
elevation of intracellular Ca2+
concentrations in human embryonic kidney
293 (HEK-293) cells expressing M-1, M-2,
or M-3 mAChRs. NSC23766 caused a
concentration-dependent rightward shift of
the carbachol concentration response
curves at all mAChRs. Thus, NSC23766 is
not only an inhibitor of Rac1 activation,
but it is within the same concentration
range a competitive antagonist at mAChRs.
Molecular docking analysis at M-2 and M-3
mAChR crystal structures confirmed this
interpretation.},
keywords = {spine remodeling contributes chronic
atrial-fibrillation small-molecule
inhibitor heart-failure rho-gtpases
i-k,i-ach channels rat cardiomyocytes
neuropathic pain g-proteins injury gpcr},
ISSN = {0022-3565},
DOI = {10.1124/Jpet.113.207266},
url = {Go to ISI://WOS:000324583600008
http://jpet.aspetjournals.org/content/347/1/69.full.pdf},
year = {2013},
type = {Journal Article}
}
x
NSC23766, a widely used inhibitor of rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors
Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(N-6-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride]. We found that NSC23766 inhibits the M-2 muscarinic acetylcholine receptor (M-2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M-2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rho-dependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M-2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly G(i)beta gamma-mediated, adenosine-induced activation of G(i) protein-regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K+ current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A(1) receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca2+ concentrations in human embryonic kidney 293 (HEK-293) cells expressing M-1, M-2, or M-3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M-2 and M-3 mAChR crystal structures confirmed this interpretation.
A. Perdih, G. Wolber, and T. Solmajer. Molecular dynamics simulation and linear interaction energy study of d-Glu-based inhibitors of the MurD ligase, J Comput Aided Mol Des, 27(8):723-738, 2013.
Links:
[doi:10.1007/S10822-013-9673-3]
[show BibTeX]
[show abstract]
x
@article{RN15,
author = {Perdih, A. and Wolber, G. and Solmajer,
T.},
title = {Molecular dynamics simulation and linear
interaction energy study of d-Glu-based
inhibitors of the MurD ligase},
journal = {Journal of Computer-Aided Molecular
Design},
volume = {27},
number = {8},
pages = {723-738},
note = {217CQ Times Cited:2 Cited References
Count:45},
abstract = {The biosynthetic pathway of the bacterial
peptidoglycan, where MurD is an enzyme
involved at the intracellular stage of its
construction, represents a collection of
highly selective macromolecular targets
for novel antibacterial drug design. In
this study as part of our investigation of
the MurD bacterial target two recently
discovered classes of the MurD ligase
inhibitors were investigated resulting
from the lead optimization phases of the
N-sulfonamide d-Glu MurD inhibitors.
Molecular dynamics simulations, based on
novel structural data, in conjunction with
the linear interaction energy (LIE) method
suggested the transferability of our
previously obtained LIE coefficients to
further d-Glu based classes of MurD
inhibitors. Analysis of the observed
dynamical behavior of these compounds in
the MurD active site was supported by
static drug design techniques. These
results complement the current knowledge
of the MurD inhibitory mechanism and
provide valuable support for the d-Glu
paradigm of the inhibitor design.},
keywords = {molecular dynamics (md) simulations
linear interaction energy (lie) method
structure-based pharmacophore models murd
ligase antibacterial agents drug design
d-glutamic acid adding enzyme kinase
inhibitors organic-molecules kinetic
mechanism binding-affinity drug design
discovery pharmacophores derivatives},
ISSN = {0920-654X},
DOI = {10.1007/S10822-013-9673-3},
url = {Go to ISI://WOS:000324334600008
http://download.springer.com/static/pdf/612/art%253A10.1007%252Fs10822-013-9673-3.pdf?auth66= 1411553415_824cfb4729b999d5c774dd2180f661a4&ext=.pdf},
year = {2013},
type = {Journal Article}
}
x
Molecular dynamics simulation and linear interaction energy study of d-Glu-based inhibitors of the MurD ligase
The biosynthetic pathway of the bacterial peptidoglycan, where MurD is an enzyme involved at the intracellular stage of its construction, represents a collection of highly selective macromolecular targets for novel antibacterial drug design. In this study as part of our investigation of the MurD bacterial target two recently discovered classes of the MurD ligase inhibitors were investigated resulting from the lead optimization phases of the N-sulfonamide d-Glu MurD inhibitors. Molecular dynamics simulations, based on novel structural data, in conjunction with the linear interaction energy (LIE) method suggested the transferability of our previously obtained LIE coefficients to further d-Glu based classes of MurD inhibitors. Analysis of the observed dynamical behavior of these compounds in the MurD active site was supported by static drug design techniques. These results complement the current knowledge of the MurD inhibitory mechanism and provide valuable support for the d-Glu paradigm of the inhibitor design.
M. Spetea, M. F. Asim, S. Noha, G. Wolber, and H. Schmidhammer. Current κ opioid receptor ligands and discovery of a new molecular scaffold as a κ opioid receptor antagonist using pharmacophore-based virtual screening, Curr Pharm Design, 19(42):7362-7372, 2013.
Links:
[doi:10.2174/138161281942140105162601]
[show BibTeX]
[show abstract]
x
@article{RN10,
author = {Spetea, M. and Asim, M. F. and Noha, S.
and Wolber, G. and Schmidhammer, H.},
title = {Current κ opioid receptor ligands and
discovery of a new molecular scaffold as a
κ opioid receptor antagonist using
pharmacophore-based virtual screening},
journal = {Current Pharmaceutical Design},
volume = {19},
number = {42},
pages = {7362-7372},
note = {Sp. Iss. SI 285YU Times Cited:1 Cited
References Count:93},
abstract = {The kappa opioid receptor (KOR) plays a
significant role in many physiological
functions, including pain relief, stress,
depression, drug abuse, anxiety and
psychotic behaviors. KORs are widely
distributed in the central and peripheral
nervous systems, and are specifically
activated by endogenous opioids derived
from prodynorphin. They are members of the
G protein-coupled receptor superfamily,
and the crystal structure of the human KOR
was recently elucidated. KORs were
initially studied for their involvement in
mediation of pain as stimulation of KOR
produces analgesia and minimizes abuse
liability and other side effects.
Nowadays, the KOR is rapidly emerging as
an important target for the treatment of a
variety of other human disorders.
Specifically, the KOR system has become
increasingly implicated as a modulator of
stress-related and addictive behaviors.
Several selective KOR partial agonists and
antagonists have been developed as
potential antidepressants, anxiolytic and
anti-addiction medications. Although many
KOR ligands have not demonstrated
desirable pharmacological properties, some
have been shown to be viable drug
candidates. Herein, we describe chemical
and pharmacological developments on KOR
ligands, advantages and challenges, and
potential therapeutic applications of
ligands for KORs. In the second part,
recent advances in the KOR drug design
utilizing computational approaches are
presented, with focus on the discovery of
a new naturally derived scaffold,
sewarine, as a novel class of selective
KOR ligands with antagonist properties,
using a pharmacophore-based virtual
screening strategy.},
keywords = {kappa opioid receptor agonist antagonist
sewarine drug design pharmacophore virtual
screening protein coupled receptors
in-silico pharmacology rhazya-stricta drug
discovery adjuvant arthritis
natural-products analgesic efficacy highly
potent agonist identification},
ISSN = {1381-6128},
DOI = {10.2174/138161281942140105162601},
url = {Go to ISI://WOS:000329431900005
http://www.eurekaselect.com/111859/article
https://www.eurekaselect.com/111859/article},
year = {2013},
type = {Journal Article}
}
x
Current κ opioid receptor ligands and discovery of a new molecular scaffold as a κ opioid receptor antagonist using pharmacophore-based virtual screening
The kappa opioid receptor (KOR) plays a significant role in many physiological functions, including pain relief, stress, depression, drug abuse, anxiety and psychotic behaviors. KORs are widely distributed in the central and peripheral nervous systems, and are specifically activated by endogenous opioids derived from prodynorphin. They are members of the G protein-coupled receptor superfamily, and the crystal structure of the human KOR was recently elucidated. KORs were initially studied for their involvement in mediation of pain as stimulation of KOR produces analgesia and minimizes abuse liability and other side effects. Nowadays, the KOR is rapidly emerging as an important target for the treatment of a variety of other human disorders. Specifically, the KOR system has become increasingly implicated as a modulator of stress-related and addictive behaviors. Several selective KOR partial agonists and antagonists have been developed as potential antidepressants, anxiolytic and anti-addiction medications. Although many KOR ligands have not demonstrated desirable pharmacological properties, some have been shown to be viable drug candidates. Herein, we describe chemical and pharmacological developments on KOR ligands, advantages and challenges, and potential therapeutic applications of ligands for KORs. In the second part, recent advances in the KOR drug design utilizing computational approaches are presented, with focus on the discovery of a new naturally derived scaffold, sewarine, as a novel class of selective KOR ligands with antagonist properties, using a pharmacophore-based virtual screening strategy.
M. Spetea, M. F. Asim, G. Wolber, and H. Schmidhammer. The µ opioid receptor and ligands acting at the µ opioid receptor as therapeutics and potential therapeutics, Curr Pharm Design, 19(42):7415-7434, 2013.
Links:
[doi:10.2174/13816128113199990362]
[show BibTeX]
[show abstract]
x
@article{RN11,
author = {Spetea, M. and Asim, M. F. and Wolber, G.
and Schmidhammer, H.},
title = {The µ opioid receptor and ligands acting
at the µ opioid receptor as therapeutics
and potential therapeutics},
journal = {Current Pharmaceutical Design},
volume = {19},
number = {42},
pages = {7415-7434},
note = {Sp. Iss. SI 285YU Times Cited:1 Cited
References Count:223},
abstract = {Although the mu opioid receptor (MOR) was
pharmacologically and biochemically
identified in binding studies forty years
ago, its structure, function, and true
complexity only have emerged after its
cloning in 1993. Continuous efforts from
many laboratories have greatly advanced
our understanding of MORs, ranging from
their anatomic distribution to cellular
and molecular mechanisms, and from cell
lines to in vivo systems. The MOR is
recognized as the main target for
effective pain relief, but its involvement
in many other physiological functions has
also been recognized. This review provides
a synopsis on the history of research on
MORs and ligands acting at the MOR with
the focus on their clinical and potential
use as therapeutic drugs, or as valuable
research tools. Since the elucidation of
the chemical structure of morphine and the
characterization of endogenous opioid
peptides, research has stimulated the
development of new generations of MOR
ligands with distinct pharmacological
profiles (agonist, antagonist, mixed
agonist/antagonist and partial agonist) or
site of action (central/peripheral).
Discovery of therapeutically useful
morphine-like drugs and innovative drugs
with new scaffolds, with several
outstanding representatives, is discussed.
Extensive efforts on modifications of
endogenous peptides to attain stable and
MOR selective analogs are overviewed with
stimulating results for the development of
peptide-based pharmaceuticals. With
pharmacophore modeling as an important
tool in drug discovery, application of
modern computational methodologies for the
development of morphinans as new MOR
ligands is described. Moreover, the
crystal structure of the MOR available
today will enable the application of
structure-based approaches to design
better drugs for the management of pain,
addiction and other human diseases, where
MORs play a key role.},
keywords = {mu opioid receptor pain agonist
antagonist morphine morphinans
pharmacophore acid-substituted derivatives
selective agonist binding protein-coupled
receptors 3rd extracellular loop
pharmacological characterization
biological evaluation opiate receptor
in-vitro drug discovery highly potent},
ISSN = {1381-6128},
DOI = {10.2174/13816128113199990362},
url = {Go to ISI://WOS:000329431900010
http://www.eurekaselect.com/108136/article
https://www.eurekaselect.com/108136/article},
year = {2013},
type = {Journal Article}
}
x
The µ opioid receptor and ligands acting at the µ opioid receptor as therapeutics and potential therapeutics
Although the mu opioid receptor (MOR) was pharmacologically and biochemically identified in binding studies forty years ago, its structure, function, and true complexity only have emerged after its cloning in 1993. Continuous efforts from many laboratories have greatly advanced our understanding of MORs, ranging from their anatomic distribution to cellular and molecular mechanisms, and from cell lines to in vivo systems. The MOR is recognized as the main target for effective pain relief, but its involvement in many other physiological functions has also been recognized. This review provides a synopsis on the history of research on MORs and ligands acting at the MOR with the focus on their clinical and potential use as therapeutic drugs, or as valuable research tools. Since the elucidation of the chemical structure of morphine and the characterization of endogenous opioid peptides, research has stimulated the development of new generations of MOR ligands with distinct pharmacological profiles (agonist, antagonist, mixed agonist/antagonist and partial agonist) or site of action (central/peripheral). Discovery of therapeutically useful morphine-like drugs and innovative drugs with new scaffolds, with several outstanding representatives, is discussed. Extensive efforts on modifications of endogenous peptides to attain stable and MOR selective analogs are overviewed with stimulating results for the development of peptide-based pharmaceuticals. With pharmacophore modeling as an important tool in drug discovery, application of modern computational methodologies for the development of morphinans as new MOR ligands is described. Moreover, the crystal structure of the MOR available today will enable the application of structure-based approaches to design better drugs for the management of pain, addiction and other human diseases, where MORs play a key role.
S. Distinto, F. Esposito, J. Kirchmair, M. C. Cardia, M. Gaspari, E. Maccioni, S. Alcaro, P. Markt, G. Wolber, L. Zinzula, and E. Tramontano. Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach, Eur J Med Chem, 50:216-229, 2012.
Links:
[doi:10.1016/J.Ejmech.2012.01.056]
[show BibTeX]
[show abstract]
x
@article{RN31,
author = {Distinto, S. and Esposito, F. and
Kirchmair, J. and Cardia, M. C. and
Gaspari, M. and Maccioni, E. and Alcaro,
S. and Markt, P. and Wolber, G. and
Zinzula, L. and Tramontano, E.},
title = {Identification of HIV-1 reverse
transcriptase dual inhibitors by a
combined shape-, 2D-fingerprint- and
pharmacophore-based virtual screening
approach},
journal = {European Journal of Medicinal Chemistry},
volume = {50},
pages = {216-229},
note = {932IP Times Cited:11 Cited References
Count:78},
abstract = {We report the first application of
ligand-based virtual screening (VS)
methods for discovering new compounds able
to inhibit both human immunodeficiency
virus type 1 (HIV-1) reverse transcriptase
(RT)-associated functions, DNA polymerase
and ribonuclease H (RNase H) activities.
The overall VS campaign consisted of two
consecutive screening processes. In the
first, the VS platform Rapid Overlay of
Chemical Structures (ROCS) was used to
perform in silico shape-based similarity
screening on the NCI compounds database in
which a hydrazone derivative, previously
shown to inhibit the HIV-1 RI, was chosen.
As a result, 34 hit molecules were
selected and assayed on both RI-associated
functions. In the second, the 4 most
potent RI inhibitors identified were
selected as queries for parallel VS
performed by combining shape-based,
2D-fingerprint and 3D-pharmacophore VS
methods. Overall, a set of molecules
characterized by new different scaffolds
were identified as novel inhibitors of
both HIV-1 RI-associated activities in the
low micromolar range. (C) 2012 Elsevier
Masson SAS. All rights reserved.},
keywords = {hiv molecular fingerprints pharmacophore
rnase h shape virtual screening rnase-h
activity ribonuclease-h molecular docking
accurate docking recent progress
binding-sites active-site replication
discovery database},
ISSN = {0223-5234},
DOI = {10.1016/J.Ejmech.2012.01.056},
url = {Go to ISI://WOS:000303284400024
http://ac.els-cdn.com/S0223523412000724/1-s2.0-S0223523412000724-main.pdf?_tid= d2a118ce-4240-11e4-a14f-00000aab0f02&acdnat=1411380870_38ae86ece5f644d61da0c34a1b013bb3},
year = {2012},
type = {Journal Article}
}
x
Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach
We report the first application of ligand-based virtual screening (VS) methods for discovering new compounds able to inhibit both human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT)-associated functions, DNA polymerase and ribonuclease H (RNase H) activities. The overall VS campaign consisted of two consecutive screening processes. In the first, the VS platform Rapid Overlay of Chemical Structures (ROCS) was used to perform in silico shape-based similarity screening on the NCI compounds database in which a hydrazone derivative, previously shown to inhibit the HIV-1 RI, was chosen. As a result, 34 hit molecules were selected and assayed on both RI-associated functions. In the second, the 4 most potent RI inhibitors identified were selected as queries for parallel VS performed by combining shape-based, 2D-fingerprint and 3D-pharmacophore VS methods. Overall, a set of molecules characterized by new different scaffolds were identified as novel inhibitors of both HIV-1 RI-associated activities in the low micromolar range. (C) 2012 Elsevier Masson SAS. All rights reserved.
S. Distinto, M. Yanez, S. Alcaro, M. C. Cardia, M. Gaspari, M. L. Sanna, R. Meleddu, F. Ortuso, J. Kirchmair, P. Markt, A. Bolasco, G. Wolber, D. Secci, and E. Maccioni. Synthesis and biological assessment of novel 2-thiazolylhydrazones and computational analysis of their recognition by monoamine oxidase B, Eur J Med Chem, 48:284-295, 2012.
Links:
[doi:10.1016/J.Ejmech.2011.12.027]
[show BibTeX]
[show abstract]
x
@article{RN35,
author = {Distinto, S. and Yanez, M. and Alcaro, S.
and Cardia, M. C. and Gaspari, M. and
Sanna, M. L. and Meleddu, R. and Ortuso,
F. and Kirchmair, J. and Markt, P. and
Bolasco, A. and Wolber, G. and Secci, D.
and Maccioni, E.},
title = {Synthesis and biological assessment of
novel 2-thiazolylhydrazones and
computational analysis of their
recognition by monoamine oxidase B},
journal = {European Journal of Medicinal Chemistry},
volume = {48},
pages = {284-295},
note = {895GT Times Cited:7 Cited References
Count:53},
abstract = {Monoamine oxidase B (MAO-B) is a
promising target for the treatment of
neurodegenerative disorders. We report the
synthesis and the biological evaluation of
halogenated derivatives of
1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines.
The fluorinated series shows interesting
activity and great selectivity toward the
human recombinant MAO-B isoform expressed
in baculovirus infected BTI insect cells.
The multiple crystal structures alignment
of the enzyme highlighted pronounced
induced fit (IF) adaptations with respect
to bound ligands. Therefore, IF docking
(IFD) experiments and molecular dynamic
(MD) simulations were carried out to
reveal the putative binding mode and to
explain the experimentally observed
differences in the activity of
1-(aryliden-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazines.
The importance of water molecules within
the binding site was also investigated.
These are known to play an important role
in the binding site cavity and to mediate
protein ligand interactions. Detailed
analyses of the trajectories provide
insights on the chemical features required
for the activity of this scaffold. In
particular it was highlighted the
importance of fluorine atom interacting
with the water close to the cofactor and
the influence of steric bulkiness of
substituents in the arylidene moiety. Free
energy perturbation (FEP) analysis
confirmed experimental data. The
information we deduced will help to
develop novel high-affinity MAO-B
inhibitors. (C) 2011 Elsevier Masson SAS.
All rights reserved.},
keywords = {fep grid induced fit docking mao-b
inhibitors molecular dynamics selective
inhibitory-activity molecular-dynamics
parkinsons-disease drug discovery
structural insights medicinal chemistry
crystal-structures binding-sites docking
mao},
ISSN = {0223-5234},
DOI = {10.1016/J.Ejmech.2011.12.027},
url = {Go to ISI://WOS:000300484900029
http://ac.els-cdn.com/S0223523411009081/1-s2.0-S0223523411009081-main.pdf?_tid= cfaf5680-4240-11e4-a5cd-00000aacb361&acdnat=1411380865_c4b345c249fcef3e4fe2ac8146c7d68f},
year = {2012},
type = {Journal Article}
}
x
Synthesis and biological assessment of novel 2-thiazolylhydrazones and computational analysis of their recognition by monoamine oxidase B
Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines. The fluorinated series shows interesting activity and great selectivity toward the human recombinant MAO-B isoform expressed in baculovirus infected BTI insect cells. The multiple crystal structures alignment of the enzyme highlighted pronounced induced fit (IF) adaptations with respect to bound ligands. Therefore, IF docking (IFD) experiments and molecular dynamic (MD) simulations were carried out to reveal the putative binding mode and to explain the experimentally observed differences in the activity of 1-(aryliden-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazines. The importance of water molecules within the binding site was also investigated. These are known to play an important role in the binding site cavity and to mediate protein ligand interactions. Detailed analyses of the trajectories provide insights on the chemical features required for the activity of this scaffold. In particular it was highlighted the importance of fluorine atom interacting with the water close to the cofactor and the influence of steric bulkiness of substituents in the arylidene moiety. Free energy perturbation (FEP) analysis confirmed experimental data. The information we deduced will help to develop novel high-affinity MAO-B inhibitors. (C) 2011 Elsevier Masson SAS. All rights reserved.
A. Faussner, S. Schussler, J. Feierler, M. Bermudez, J. Pfeifer, K. Schnatbaum, T. Tradler, M. Jochum, G. Wolber, and C. Gibson. Binding characteristics of [3H]-JSM10292: A new cell membrane-permeant non-peptide bradykinin B2 receptor antagonist, Br J Pharmacol, 167(4):839-853, 2012.
Links:
[doi:10.1111/J.1476-5381.2012.02054.X]
[show BibTeX]
[show abstract]
x
@article{RN24,
author = {Faussner, A. and Schussler, S. and
Feierler, J. and Bermudez, M. and Pfeifer,
J. and Schnatbaum, K. and Tradler, T. and
Jochum, M. and Wolber, G. and Gibson, C.},
title = {Binding characteristics of [3H]-JSM10292:
A new cell membrane-permeant non-peptide
bradykinin B2 receptor antagonist},
journal = {British Journal of Pharmacology},
volume = {167},
number = {4},
pages = {839-853},
note = {014SN Times Cited:1 Cited References
Count:34},
abstract = {BACKGROUND AND PURPOSE A 3H-labelled
derivative of the novel small-molecule
bradykinin (BK) B2 receptor antagonist
JSM10292 was used to directly study its
binding properties to human and animal B2
receptors in intact cells and to closely
define its binding site. EXPERIMENTAL
APPROACH Equilibrium binding, dissociation
and competition studies with various B2
receptor ligands and [3H]-JSM10292 were
performed at 4 degrees C and 37 degrees C.
The experiments were carried out using
HEK293 cells stably (over)expressing
wild-type and mutant B2 receptors of human
and animal origin. KEY RESULTS
[3H]-JSM10292 bound to B2 receptors at 4
degrees C and at 37 degrees C with the
same high affinity. Its dissociation
strongly depended on the temperature and
increased when unlabelled B2 receptor
agonists or antagonists were added.
[3H]-JSM10292 is cell membrane-permeant
and thus also bound to intracellular,
active B2 receptors, as indicated by the
different nonspecific binding in the
presence of unlabelled JSM10292 or of
membrane-impermeant BK. Equilibrium
binding curves with [3H]-JSM10292 and
competition experiments with unlabelled
JSM10292 and [3H]-BK showed a different
affinity profile for the wild-type B2
receptor in different species (man,
cynomolgus, rabbit, mouse, rat, dog, pig,
guinea pig). Characterization of B2
receptor mutants and species orthologues
combined with homology modelling, using
the CXCR4 as template, suggests that the
binding site of JSM10292 is different from
that of BK but overlaps with that of
MEN16132, another small non-peptide B2
receptor ligand. CONCLUSIONS AND
IMPLICATIONS [3H]-JSM10292 is a novel,
cell membrane-permeant, high-affinity B2
receptor antagonist that allows direct in
detail studies of active, surface and
intracellularly located wild-type and
mutant B2 receptors.},
keywords = {cell membrane-permeant radiolabelled
non-peptide antagonist bradykinin b2
receptor small molecule compound binding
site gpcr kinin b-2 receptor
pharmacological characterization
mutational analysis genetic algorithm
helix 8 phosphorylation internalization
pharmacophores sequestration recognition},
ISSN = {0007-1188},
DOI = {10.1111/J.1476-5381.2012.02054.X},
url = {Go to ISI://WOS:000309396100013
http://onlinelibrary.wiley.com/store/10.1111/j.1476-5381.2012.02054.x/asset/j.1476-5381.2012.02054.x.pdf?v= 1&t=i0dnmrs5&s=0ec305f1063dfe790f7a2db2a4d72745d61a878e},
year = {2012},
type = {Journal Article}
}
x
Binding characteristics of [3H]-JSM10292: A new cell membrane-permeant non-peptide bradykinin B2 receptor antagonist
BACKGROUND AND PURPOSE A 3H-labelled derivative of the novel small-molecule bradykinin (BK) B2 receptor antagonist JSM10292 was used to directly study its binding properties to human and animal B2 receptors in intact cells and to closely define its binding site. EXPERIMENTAL APPROACH Equilibrium binding, dissociation and competition studies with various B2 receptor ligands and [3H]-JSM10292 were performed at 4 degrees C and 37 degrees C. The experiments were carried out using HEK293 cells stably (over)expressing wild-type and mutant B2 receptors of human and animal origin. KEY RESULTS [3H]-JSM10292 bound to B2 receptors at 4 degrees C and at 37 degrees C with the same high affinity. Its dissociation strongly depended on the temperature and increased when unlabelled B2 receptor agonists or antagonists were added. [3H]-JSM10292 is cell membrane-permeant and thus also bound to intracellular, active B2 receptors, as indicated by the different nonspecific binding in the presence of unlabelled JSM10292 or of membrane-impermeant BK. Equilibrium binding curves with [3H]-JSM10292 and competition experiments with unlabelled JSM10292 and [3H]-BK showed a different affinity profile for the wild-type B2 receptor in different species (man, cynomolgus, rabbit, mouse, rat, dog, pig, guinea pig). Characterization of B2 receptor mutants and species orthologues combined with homology modelling, using the CXCR4 as template, suggests that the binding site of JSM10292 is different from that of BK but overlaps with that of MEN16132, another small non-peptide B2 receptor ligand. CONCLUSIONS AND IMPLICATIONS [3H]-JSM10292 is a novel, cell membrane-permeant, high-affinity B2 receptor antagonist that allows direct in detail studies of active, surface and intracellularly located wild-type and mutant B2 receptors.
L. Guasch, E. Sala, A. Castell-Auvi, L. Cedo, K. R. Liedl, G. Wolber, M. Muehlbacher, M. Mulero, M. Pinent, A. Ardevol, C. Valls, G. Pujadas, and S. Garcia-Vallve. Identification of PPARγ partial agonists of natural origin (I): Development of a virtual screening procedure and in vitro validation, Plos One, 7(11):e50816, 2012.
Links:
[doi:10.1371/journal.pone.0050816]
[show BibTeX]
[show abstract]
x
@article{RN22,
author = {Guasch, L. and Sala, E. and Castell-Auvi,
A. and Cedo, L. and Liedl, K. R. and
Wolber, G. and Muehlbacher, M. and Mulero,
M. and Pinent, M. and Ardevol, A. and
Valls, C. and Pujadas, G. and
Garcia-Vallve, S.},
title = {Identification of PPARγ partial agonists
of natural origin (I): Development of a
virtual screening procedure and in vitro
validation},
journal = {Plos One},
volume = {7},
number = {11},
pages = {e50816},
note = {054WM Times Cited:4 Cited References
Count:46},
abstract = {Background: Although there are successful
examples of the discovery of new PPAR
gamma agonists, it has recently been of
great interest to identify new PPAR gamma
partial agonists that do not present the
adverse side effects caused by PPAR gamma
full agonists. Consequently, the goal of
this work was to design, apply and
validate a virtual screening workflow to
identify novel PPAR gamma partial agonists
among natural products.
Methodology/Principal Findings: We have
developed a virtual screening procedure
based on structure-based pharmacophore
construction, protein-ligand docking and
electrostatic/shape similarity to discover
novel scaffolds of PPAR gamma partial
agonists. From an initial set of 89,165
natural products and natural product
derivatives, 135 compounds were identified
as potential PPAR gamma partial agonists
with good ADME properties. Ten compounds
that represent ten new chemical scaffolds
for PPAR gamma partial agonists were
selected for in vitro biological testing,
but two of them were not assayed due to
solubility problems. Five out of the
remaining eight compounds were confirmed
as PPAR gamma partial agonists: they bind
to PPAR gamma do not or only moderately
stimulate the transactivation activity of
PPAR gamma do not induce adipogenesis of
preadipocyte cells and stimulate the
insulin-induced glucose uptake of
adipocytes. Conclusions/Significance: We
have demonstrated that our virtual
screening protocol was successful in
identifying novel scaffolds for PPAR gamma
partial agonists.},
keywords = {gamma partial agonists
proliferator-activated-receptors
ppar-gamma nuclear receptors drug
discovery next-generation binding ligands
modulators insights},
ISSN = {1932-6203},
DOI = {10.1371/journal.pone.0050816},
url = {Go to ISI://WOS:000312376100202
http://www.plosone.org/article/fetchObject.action?uri= info%3Adoi%2F10.1371%2Fjournal.pone.0050816&representation=PDF},
year = {2012},
type = {Journal Article}
}
x
Identification of PPARγ partial agonists of natural origin (I): Development of a virtual screening procedure and in vitro validation
Background: Although there are successful examples of the discovery of new PPAR gamma agonists, it has recently been of great interest to identify new PPAR gamma partial agonists that do not present the adverse side effects caused by PPAR gamma full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPAR gamma partial agonists among natural products. Methodology/Principal Findings: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPAR gamma partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPAR gamma partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPAR gamma partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPAR gamma partial agonists: they bind to PPAR gamma do not or only moderately stimulate the transactivation activity of PPAR gamma do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPAR gamma partial agonists.
J. Mortier, C. Rakers, R. Frederick, and G. Wolber. Computational tools for in silico fragment-based drug design, Curr Top Med Chem, 12(17):1935-1943, 2012.
Links:
[show BibTeX]
[show abstract]
x
@article{RN25,
author = {Mortier, J. and Rakers, C. and Frederick,
R. and Wolber, G.},
title = {Computational tools for in silico
fragment-based drug design},
journal = {Current Topics in Medicinal Chemistry},
volume = {12},
number = {17},
pages = {1935-1943},
note = {069IW Times Cited:5 Cited References
Count:97},
abstract = {Fragment-based strategy in drug design
involves the initial discovery of
low-molecular mass molecules. Owing to
their small-size, fragments are molecular
tools to probe specific sub-pockets within
a protein active site. Once their
interaction within the enzyme cavity is
clearly understood and experimentally
validated, they represent a unique
opportunity to design potent and efficient
larger compounds. Computer-aided methods
can essentially support the identification
of suitable fragments. In this review,
available tools for computational drug
design are discussed in the frame of
fragment-based approaches. We analyze and
review (i) available commercial fragment
libraries with respect to their properties
and size, (ii) computational methods for
the construction of such a library, (iii)
the different strategies and software
packages for the selection of the
fragments with predicted affinity to a
given target, and (iv) tools for the in
silico linkage of fragments into an actual
high-affinity lead structure candidate.},
keywords = {fragment-based design libraries software
molecular modelling rule of three fragment
linkage de-novo design protein
active-sites lead discovery molecular
complexity accurate docking combinatorial
chemistry 3-dimensional structure receptor
antagonists chemical fragments genetic
algorithm},
ISSN = {1568-0266},
url = {Go to ISI://WOS:000313429600009},
year = {2012},
type = {Journal Article}
}
x
Computational tools for in silico fragment-based drug design
Fragment-based strategy in drug design involves the initial discovery of low-molecular mass molecules. Owing to their small-size, fragments are molecular tools to probe specific sub-pockets within a protein active site. Once their interaction within the enzyme cavity is clearly understood and experimentally validated, they represent a unique opportunity to design potent and efficient larger compounds. Computer-aided methods can essentially support the identification of suitable fragments. In this review, available tools for computational drug design are discussed in the frame of fragment-based approaches. We analyze and review (i) available commercial fragment libraries with respect to their properties and size, (ii) computational methods for the construction of such a library, (iii) the different strategies and software packages for the selection of the fragments with predicted affinity to a given target, and (iv) tools for the in silico linkage of fragments into an actual high-affinity lead structure candidate.
M. S. Murgueitio, M. Bermudez, J. Mortier, and G. Wolber. In silico virtual screening approaches for anti-viral drug discovery, Drug Discovery Today: Technologies, 9(3):e219-25, 2012.
Links:
[doi:10.1016/j.ddtec.2012.07.009]
[show BibTeX]
[show abstract]
x
@article{RN127,
author = {Murgueitio, M. S. and Bermudez, M. and
Mortier, J. and Wolber, G.},
title = {In silico virtual screening approaches
for anti-viral drug discovery},
journal = {Drug Discovery Today: Technologies},
volume = {9},
number = {3},
pages = {e219-25},
note = {Murgueitio, Manuela S Bermudez, Marcel
Mortier, Jeremie Wolber, Gerhard eng
England 2012/10/01 00:00 Drug Discov Today
Technol. 2012 Autumn;9(3):e219-25. doi:
10.1016/j.ddtec.2012.07.009.},
abstract = {Despite the considerable advances in
medical and pharmaceutical research during
the past years, diseases caused by viruses
have remained a major burden to public
health. Virtual in silico screening has
repeatedly proven to be useful to meet the
special challenges of antiviral drug
discovery. Large virtual compound
libraries are filtered by different
computational screening methods such as
docking, ligand-based similarity searches
or pharmacophore-based screening, reducing
the number of candidate molecules to a
smaller set of promising candidates that
are then tested biologically. This
rational approach makes the drug discovery
process more goal-oriented and saves
resources in terms of time and money. In
this review we discuss how different
virtual screening techniques can be
applied to antiviral drug discovery,
present recent success stories in this
field and finally address the main
differences between the methods.:},
ISSN = {1740-6749 (Electronic) 1740-6749
(Linking)},
DOI = {10.1016/j.ddtec.2012.07.009},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24990575
http://ac.els-cdn.com/S1740674912000492/1-s2.0-S1740674912000492-main.pdf?_tid= cb79d2a2-4240-11e4-8cca-00000aacb360&acdnat=1411380858_da495ce55c81d16090c75028d80b953c},
year = {2012},
type = {Journal Article}
}
x
In silico virtual screening approaches for anti-viral drug discovery
Despite the considerable advances in medical and pharmaceutical research during the past years, diseases caused by viruses have remained a major burden to public health. Virtual in silico screening has repeatedly proven to be useful to meet the special challenges of antiviral drug discovery. Large virtual compound libraries are filtered by different computational screening methods such as docking, ligand-based similarity searches or pharmacophore-based screening, reducing the number of candidate molecules to a smaller set of promising candidates that are then tested biologically. This rational approach makes the drug discovery process more goal-oriented and saves resources in terms of time and money. In this review we discuss how different virtual screening techniques can be applied to antiviral drug discovery, present recent success stories in this field and finally address the main differences between the methods.:
S. M. Noha, B. Jazzar, S. Kuehnl, J. M. Rollinger, H. Stuppner, A. M. Schaible, O. Werz, G. Wolber, and D. Schuster. Pharmacophore-based discovery of a novel cytosolic phospholipase A(2)alpha inhibitor, Bioorg Med Chem Lett, 22(2):1202-1207, 2012.
Links:
[doi:10.1016/J.Bmcl.2011.11.093]
[show BibTeX]
[show abstract]
x
@article{RN36,
author = {Noha, S. M. and Jazzar, B. and Kuehnl, S.
and Rollinger, J. M. and Stuppner, H. and
Schaible, A. M. and Werz, O. and Wolber,
G. and Schuster, D.},
title = {Pharmacophore-based discovery of a novel
cytosolic phospholipase A(2)alpha
inhibitor},
journal = {Bioorganic & Medicinal Chemistry
Letters},
volume = {22},
number = {2},
pages = {1202-1207},
note = {883RY Times Cited:2 Cited References
Count:31},
abstract = {The release of arachidonic acid, a
precursor in the production of
prostaglandins and leukotrienes, is
achieved by activity of the cytosolic
phospholipase A(2)alpha (cPLA(2)alpha).
Signaling mediated by this class of
bioactive lipids, which are collectively
referred to as eicosanoids, has numerous
effects in physiological and pathological
processes. Herein, we report the
development of a ligand-based
pharmacophore model and
pharmacophore-based virtual screening of
the National Cancer Institute (NCI)
database, leading to the identification of
4-(hexadecyloxy)-3-(2-(hydroxyimino)-3-oxobutanamido)benzoic
acid (NSC 119957) as cPLA(2)alpha
inhibitor in cell-free and cell-based in
vitro assays. (C) 2011 Elsevier Ltd. All
rights reserved.},
keywords = {cytosolic phospholipase a(2)alpha
cpla(2)alpha inflammation pharmacophore
modeling virtual screening in-vitro
metabolic stability biological-activity
a(2) inhibitors drug discovery design vivo
lipophilicity solubility cells},
ISSN = {0960-894X},
DOI = {10.1016/J.Bmcl.2011.11.093},
url = {Go to ISI://WOS:000299653500089
http://ac.els-cdn.com/S0960894X11016374/1-s2.0-S0960894X11016374-main.pdf?_tid= c508eafc-4240-11e4-831f-00000aacb362&acdnat=1411380847_7772547812e66f831632451579fb21ab},
year = {2012},
type = {Journal Article}
}
x
Pharmacophore-based discovery of a novel cytosolic phospholipase A(2)alpha inhibitor
The release of arachidonic acid, a precursor in the production of prostaglandins and leukotrienes, is achieved by activity of the cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Signaling mediated by this class of bioactive lipids, which are collectively referred to as eicosanoids, has numerous effects in physiological and pathological processes. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the National Cancer Institute (NCI) database, leading to the identification of 4-(hexadecyloxy)-3-(2-(hydroxyimino)-3-oxobutanamido)benzoic acid (NSC 119957) as cPLA(2)alpha inhibitor in cell-free and cell-based in vitro assays. (C) 2011 Elsevier Ltd. All rights reserved.
R. Ottana, R. Maccari, S. Amuso, G. Wolber, D. Schuster, S. Herdlinger, G. Manao, G. Camici, and P. Paoli. New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells, Eur J Med Chem, 50:332-343, 2012.
Links:
[doi:10.1016/J.Ejmech.2012.02.012]
[show BibTeX]
[show abstract]
x
@article{RN30,
author = {Ottana, R. and Maccari, R. and Amuso, S.
and Wolber, G. and Schuster, D. and
Herdlinger, S. and Manao, G. and Camici,
G. and Paoli, P.},
title = {New
4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic
acids active as protein tyrosine
phosphatase inhibitors endowed with
insulinomimetic effect on mouse C2C12
skeletal muscle cells},
journal = {European Journal of Medicinal Chemistry},
volume = {50},
pages = {332-343},
note = {932IP Times Cited:9 Cited References
Count:73},
abstract = {In pursuing our research targeting the
identification of potent inhibitors of
PTP1B and LMW-PTP, we have identified new
4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic
acids endowed with interesting in vitro
inhibitory profiles. Most compounds proved
to be inhibitors of PTP1B and LMW-PTP
isoform IF1. The tested inhibitors also
showed selectivity towards PTP1B over the
closely related TC-PTP. These compounds
were found to activate the
insulin-mediated signalling on mouse C2C12
skeletal muscle cells by increasing the
phosphorylation levels of the insulin
receptor and promoting cellular
2-deoxyglucose uptake. Interestingly,
4-{[5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylmino)-4-oxo-3-thiazolidinyl]methyl}benzoic
acid (7d), the best in vitro inhibitor of
PTP1B and the isoform IF1 of LMW-PTP,
provided the highest activation level of
the insulin receptor and was found to be
endowed with an excellent insulinomimetic
effect on the selected cells. This
compound therefore represents an
interesting lead compound for developing
novel PTP1B and LMW-PTP inhibitors which
could be achieved by improving both its
pharmacological profile and its
potentiating effects on insulin
signalling. (C) 2012 Elsevier Masson SAS.
All rights reserved.},
keywords = {enzyme inhibitor diabetes mellitus
obesity protein tyrosine phosphatase
insulinomimetic agent molecular docking
weight phosphotyrosyl phosphatase
structure-based optimization insulin
sensitivity signal-transduction obese mice
lmw-ptp negative regulator genetic
algorithm crystal-structure 1b
inhibitors},
ISSN = {0223-5234},
DOI = {10.1016/J.Ejmech.2012.02.012},
url = {Go to ISI://WOS:000303284400036
http://ac.els-cdn.com/S0223523412000888/1-s2.0-S0223523412000888-main.pdf?_tid= bdc34d1e-4240-11e4-9ceb-00000aacb35f&acdnat=1411380835_4d4b004d734d58a8eb4953f4383b947a},
year = {2012},
type = {Journal Article}
}
x
New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells
In pursuing our research targeting the identification of potent inhibitors of PTP1B and LMW-PTP, we have identified new 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids endowed with interesting in vitro inhibitory profiles. Most compounds proved to be inhibitors of PTP1B and LMW-PTP isoform IF1. The tested inhibitors also showed selectivity towards PTP1B over the closely related TC-PTP. These compounds were found to activate the insulin-mediated signalling on mouse C2C12 skeletal muscle cells by increasing the phosphorylation levels of the insulin receptor and promoting cellular 2-deoxyglucose uptake. Interestingly, 4-{[5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylmino)-4-oxo-3-thiazolidinyl]methyl}benzoic acid (7d), the best in vitro inhibitor of PTP1B and the isoform IF1 of LMW-PTP, provided the highest activation level of the insulin receptor and was found to be endowed with an excellent insulinomimetic effect on the selected cells. This compound therefore represents an interesting lead compound for developing novel PTP1B and LMW-PTP inhibitors which could be achieved by improving both its pharmacological profile and its potentiating effects on insulin signalling. (C) 2012 Elsevier Masson SAS. All rights reserved.
S. Santos-Sierra, J. Kirchmair, A. M. Perna, D. Reiss, K. Kemter, W. Roschinger, H. Glossmann, S. W. Gersting, A. C. Muntau, G. Wolber, and F. B. Lagler. Novel pharmacological chaperones that correct phenylketonuria in mice, Hum Mol Genet, 21(8):1877-1887, 2012.
Links:
[doi:10.1093/Hmg/Dds001]
[show BibTeX]
[show abstract]
x
@article{RN29,
author = {Santos-Sierra, S. and Kirchmair, J. and
Perna, A. M. and Reiss, D. and Kemter, K.
and Roschinger, W. and Glossmann, H. and
Gersting, S. W. and Muntau, A. C. and
Wolber, G. and Lagler, F. B.},
title = {Novel pharmacological chaperones that
correct phenylketonuria in mice},
journal = {Human Molecular Genetics},
volume = {21},
number = {8},
pages = {1877-1887},
note = {919DS Times Cited:11 Cited References
Count:70},
abstract = {Phenylketonuria (PKU) is caused by
inherited phenylalanine-hydroxylase (PAH)
deficiency and, in many genotypes, it is
associated with protein misfolding. The
natural cofactor of PAH,
tetrahydrobiopterin (BH4), can act as a
pharmacological chaperone (PC) that
rescues enzyme function. However, BH4
shows limited efficacy in some PKU
genotypes and its chemical synthesis is
very costly. Taking an integrated drug
discovery approach which has not been
applied to this target before, we
identified alternative PCs for the
treatment of PKU. Shape-focused virtual
screening of the National Cancer
Institutes chemical library identified 84
candidate molecules with potential to bind
to the active site of PAH. An in vitro
evaluation of these yielded six compounds
that restored the enzymatic activity of
the unstable PAHV106A variant and
increased its stability in cell-based
assays against proteolytic degradation.
During a 3-day treatment study, two
compounds (benzylhydantoin and
6-amino-5-(benzylamino)-uracil)
substantially improved the in vivo Phe
oxidation and blood Phe concentrations of
PKU mice (Pah(enu1)). Notably,
benzylhydantoin was twice as effective as
tetrahydrobiopterin. In conclusion, we
identified two PCs with high in vivo
efficacy that may be further developed
into a more effective drug treatment of
PKU.},
keywords = {phenylalanine-hydroxylase deficiency
surface-plasmon resonance neutral
amino-acids ammonia-lyase mouse model
in-vivo pyrimidine cofactors
hepatoma-cells active-site
tetrahydrobiopterin},
ISSN = {0964-6906},
DOI = {10.1093/Hmg/Dds001},
url = {Go to ISI://WOS:000302302400016
http://hmg.oxfordjournals.org/content/21/8/1877.full.pdf},
year = {2012},
type = {Journal Article}
}
x
Novel pharmacological chaperones that correct phenylketonuria in mice
Phenylketonuria (PKU) is caused by inherited phenylalanine-hydroxylase (PAH) deficiency and, in many genotypes, it is associated with protein misfolding. The natural cofactor of PAH, tetrahydrobiopterin (BH4), can act as a pharmacological chaperone (PC) that rescues enzyme function. However, BH4 shows limited efficacy in some PKU genotypes and its chemical synthesis is very costly. Taking an integrated drug discovery approach which has not been applied to this target before, we identified alternative PCs for the treatment of PKU. Shape-focused virtual screening of the National Cancer Institutes chemical library identified 84 candidate molecules with potential to bind to the active site of PAH. An in vitro evaluation of these yielded six compounds that restored the enzymatic activity of the unstable PAHV106A variant and increased its stability in cell-based assays against proteolytic degradation. During a 3-day treatment study, two compounds (benzylhydantoin and 6-amino-5-(benzylamino)-uracil) substantially improved the in vivo Phe oxidation and blood Phe concentrations of PKU mice (Pah(enu1)). Notably, benzylhydantoin was twice as effective as tetrahydrobiopterin. In conclusion, we identified two PCs with high in vivo efficacy that may be further developed into a more effective drug treatment of PKU.
A. Schafer, A. Wellner, M. Strauss, A. Schafer, G. Wolber, and R. Gust. Influence of chlorine or fluorine substitution on the estrogenic properties of 1-alkyl-2,3,5-tris(4-hydroxyphenyl)-1h-pyrroles, J Med Chem, 55(22):9607-9618, 2012.
Links:
[show BibTeX]
[show abstract]
x
@article{RN23,
author = {Schafer, A. and Wellner, A. and Strauss,
M. and Schafer, A. and Wolber, G. and
Gust, R.},
title = {Influence of chlorine or fluorine
substitution on the estrogenic properties
of
1-alkyl-2,3,5-tris(4-hydroxyphenyl)-1h-pyrroles},
journal = {Journal of Medicinal Chemistry},
volume = {55},
number = {22},
pages = {9607-9618},
note = {042HE Times Cited:3 Cited References
Count:42},
abstract = {In continuation of Our previous work,
several 1-
alkyl-2,3,5-tris(4-hydroxyphenyl)aryl-1H-pyrroles
with chlor-Me or fluorine substituents in
the aryl residues were synthesized and
tested for estrogen receptor (ER) binding
at isolated ER alpha/ER beta. receptors
(HAP assay), and. in trans activation
assays using ER alpha-positive MCF-7/2a as
well as U2-OS/ER alpha and U2-OS/ER beta
cells. In the competition experiment at ER
alpha the compounds displayed very high
relative binding-affinities of up to 37%
(determined for 8m) but with restricted
subtype selectivity (e.g., ER alpha/ER
beta (8ma) = 9). The highest estrogenic
potency in ER alpha-positive MCP-7/2a
cells was determined for
2,3,5-tris(2-fluoro-4-hydroxyphenyl)-1-prolayl-1H-pyriole
8m (EC50 = 23 nM), while in U2-OS/ER alpha
cells
2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1H
propyl-1H pyrrole 8b (EC50 = 0.12 nM) was
the Most potent agonist, only 30 fold less
active than estradiol (E2, EC50 = 0.004
nM). In U2-OS/ER beta cells for all
pyrroles no transactivation could be
observed, which indicates that they are
selective ER alpha agonists in Cellular
systems.},
keywords = {receptor-alpha er-beta breast-cancer
mammary-gland binding mode mcf-7 cells
part 5 ligands expression agonists},
ISSN = {0022-2623},
url = {Go to ISI://WOS:000311461500017
http://pubs.acs.org/doi/pdfplus/10.1021/jm300860j},
year = {2012},
type = {Journal Article}
}
x
Influence of chlorine or fluorine substitution on the estrogenic properties of 1-alkyl-2,3,5-tris(4-hydroxyphenyl)-1h-pyrroles
In continuation of Our previous work, several 1- alkyl-2,3,5-tris(4-hydroxyphenyl)aryl-1H-pyrroles with chlor-Me or fluorine substituents in the aryl residues were synthesized and tested for estrogen receptor (ER) binding at isolated ER alpha/ER beta. receptors (HAP assay), and. in trans activation assays using ER alpha-positive MCF-7/2a as well as U2-OS/ER alpha and U2-OS/ER beta cells. In the competition experiment at ER alpha the compounds displayed very high relative binding-affinities of up to 37% (determined for 8m) but with restricted subtype selectivity (e.g., ER alpha/ER beta (8ma) = 9). The highest estrogenic potency in ER alpha-positive MCP-7/2a cells was determined for 2,3,5-tris(2-fluoro-4-hydroxyphenyl)-1-prolayl-1H-pyriole 8m (EC50 = 23 nM), while in U2-OS/ER alpha cells 2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1H propyl-1H pyrrole 8b (EC50 = 0.12 nM) was the Most potent agonist, only 30 fold less active than estradiol (E2, EC50 = 0.004 nM). In U2-OS/ER beta cells for all pyrroles no transactivation could be observed, which indicates that they are selective ER alpha agonists in Cellular systems.
S. von Grafenstein, J. Mihaly-Bison, G. Wolber, V. N. Bochkov, K. R. Liedl, and D. Schuster. Identification of Novel Liver X Receptor Activators by Structure-Based Modeling, J Chem Inf Model, 52(5):1391-1400, 2012.
Links:
[doi:10.1021/Ci300096c]
[show BibTeX]
[show abstract]
x
@article{RN28,
author = {von Grafenstein, S. and Mihaly-Bison, J.
and Wolber, G. and Bochkov, V. N. and
Liedl, K. R. and Schuster, D.},
title = {Identification of Novel Liver X Receptor
Activators by Structure-Based Modeling},
journal = {Journal of Chemical Information and
Modeling},
volume = {52},
number = {5},
pages = {1391-1400},
note = {946VN Times Cited:2 Cited References
Count:62},
abstract = {Liver X receptors (LXRs) are members of
the nuclear receptor family. Activators of
LXRs are of high pharmacological interest
as LXRs regulate cholesterol, fatty acid,
and carbohydrate metabolism as well as
inflammatory processes. On the basis of
different X-ray crystal structures, we
established a virtual screening workflow
for the identification of novel LXR
modulators. A two-step screening concept
to identify active compounds included
3D-pharmacophore filters and rescoring by
shape alignment. Eighteen virtual hits
were tested in vitro applying a reporter
gene assay, where concentration-dependent
activity was proven for four novel lead
structures. The most active compound 10, a
1,4-naphthochinone, has an estimated EC50
of around 5 mu M.},
keywords = {ligand-binding domain protein data-bank
lxr-alpha crystal-structure
immune-response tertiary-amines agonists
beta discovery atherosclerosis},
ISSN = {1549-9596},
DOI = {10.1021/Ci300096c},
url = {Go to ISI://WOS:000304385700030
http://pubs.acs.org/doi/pdfplus/10.1021/ci300096c},
year = {2012},
type = {Journal Article}
}
x
Identification of Novel Liver X Receptor Activators by Structure-Based Modeling
Liver X receptors (LXRs) are members of the nuclear receptor family. Activators of LXRs are of high pharmacological interest as LXRs regulate cholesterol, fatty acid, and carbohydrate metabolism as well as inflammatory processes. On the basis of different X-ray crystal structures, we established a virtual screening workflow for the identification of novel LXR modulators. A two-step screening concept to identify active compounds included 3D-pharmacophore filters and rescoring by shape alignment. Eighteen virtual hits were tested in vitro applying a reporter gene assay, where concentration-dependent activity was proven for four novel lead structures. The most active compound 10, a 1,4-naphthochinone, has an estimated EC50 of around 5 mu M.
U. Grienke, J. Mihaly-Bison, D. Schuster, T. Afonyushkin, M. Binder, S. H. Guan, C. R. Cheng, G. Wolber, H. Stuppner, D. A. Guo, V. N. Bochkov, and J. M. Rollinger. Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum, Bioorg Med Chem, 19(22):6779-6791, 2011.
Links:
[doi:10.1016/J.Bmc.2011.09.039]
[show BibTeX]
[show abstract]
x
@article{RN39,
author = {Grienke, U. and Mihaly-Bison, J. and
Schuster, D. and Afonyushkin, T. and
Binder, M. and Guan, S. H. and Cheng, C.
R. and Wolber, G. and Stuppner, H. and
Guo, D. A. and Bochkov, V. N. and
Rollinger, J. M.},
title = {Pharmacophore-based discovery of
FXR-agonists. Part II: Identification of
bioactive triterpenes from Ganoderma
lucidum},
journal = {Bioorganic & Medicinal Chemistry},
volume = {19},
number = {22},
pages = {6779-6791},
note = {841TI Times Cited:10 Cited References
Count:54},
abstract = {The farnesoid X receptor (FXR) belonging
to the metabolic subfamily of nuclear
receptors is a ligand-induced
transcriptional activator. Its central
function is the physiological maintenance
of bile acid homeostasis including the
regulation of glucose and lipid
metabolism. Accessible structural
information about its ligand-binding
domain renders FXR an attractive target
for in silico approaches. Integrated to
natural product research these
computational tools assist to find novel
bioactive compounds showing beneficial
effects in prevention and treatment of,
for example, the metabolic syndrome,
dyslipidemia, atherosclerosis, and type 2
diabetes. Virtual screening experiments of
our in-house Chinese Herbal Medicine
database with structure-based
pharmacophore models, previously generated
and validated, revealed mainly
lanostane-type triterpenes of the TCM
fungus Ganoderma lucidum Karst. as
putative FXR ligands. To verify the
prediction of the in silico approach, two
Ganoderma fruit body extracts and
compounds isolated thereof were
pharmacologically investigated. Pronounced
FXR-inducing effects were observed for the
extracts at a concentration of 100 mu
g/mL. Intriguingly, five lanostanes out of
25 secondary metabolites from G. lucidum,
that is, ergosterol peroxide (2),
lucidumol A (11), ganoderic acid TR (12),
ganodermanontriol (13), and ganoderiol F
(14), dose-dependently induced FXR in the
low micromolar range in a reporter gene
assay. To rationalize the binding
interactions, additional pharmacophore
profiling and molecular docking studies
were performed, which allowed establishing
a first structure-activity relationship of
the investigated triterpenes. (C) 2011
Elsevier Ltd. All rights reserved.},
keywords = {farnesoid x receptor ganoderma lucidum
lanostane triterpenes ganoderic acids
molecular modeling virtual screening
natural products farnesoid-x-receptor
bile-acid receptor natural-product
guggulsterone orphan nuclear receptor
hyperlipidemic rats gene-expression marine
sponge potent ligand activation},
ISSN = {0968-0896},
DOI = {10.1016/J.Bmc.2011.09.039},
url = {Go to ISI://WOS:000296535900028
http://ac.els-cdn.com/S0968089611007747/1-s2.0-S0968089611007747-main.pdf?_tid= ecdb5704-4240-11e4-b338-00000aab0f6b&acdnat=1411380914_67b6f8e2669729c8ceaa125f56154535},
year = {2011},
type = {Journal Article}
}
x
Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum
The farnesoid X receptor (FXR) belonging to the metabolic subfamily of nuclear receptors is a ligand-induced transcriptional activator. Its central function is the physiological maintenance of bile acid homeostasis including the regulation of glucose and lipid metabolism. Accessible structural information about its ligand-binding domain renders FXR an attractive target for in silico approaches. Integrated to natural product research these computational tools assist to find novel bioactive compounds showing beneficial effects in prevention and treatment of, for example, the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. Virtual screening experiments of our in-house Chinese Herbal Medicine database with structure-based pharmacophore models, previously generated and validated, revealed mainly lanostane-type triterpenes of the TCM fungus Ganoderma lucidum Karst. as putative FXR ligands. To verify the prediction of the in silico approach, two Ganoderma fruit body extracts and compounds isolated thereof were pharmacologically investigated. Pronounced FXR-inducing effects were observed for the extracts at a concentration of 100 mu g/mL. Intriguingly, five lanostanes out of 25 secondary metabolites from G. lucidum, that is, ergosterol peroxide (2), lucidumol A (11), ganoderic acid TR (12), ganodermanontriol (13), and ganoderiol F (14), dose-dependently induced FXR in the low micromolar range in a reporter gene assay. To rationalize the binding interactions, additional pharmacophore profiling and molecular docking studies were performed, which allowed establishing a first structure-activity relationship of the investigated triterpenes. (C) 2011 Elsevier Ltd. All rights reserved.
J. Kirchmair, S. Distinto, K. R. Liedl, P. Markt, J. M. Rollinger, D. Schuster, G. M. Spitzer, and G. Wolber. Development of anti-viral agents using molecular modeling and virtual screening techniques, Infect Disord Drug Targets, 11(1):64-93, 2011.
Links:
[doi:10.2174/187152611794407782]
[show BibTeX]
x
@article{RN145,
author = {Kirchmair, J. and Distinto, S. and Liedl,
K. R. and Markt, P. and Rollinger, J. M.
and Schuster, D. and Spitzer, G. M. and
Wolber, G.},
title = {Development of anti-viral agents using
molecular modeling and virtual screening
techniques},
journal = {Infectious disorders drug targets},
volume = {11},
number = {1},
pages = {64-93},
ISSN = {2212-3989},
DOI = {10.2174/187152611794407782},
url = {http://www.eurekaselect.com/76753/article},
year = {2011},
type = {Journal Article}
}
D. V. Kratschmar, A. Vuorinen, T. Da Cunha, G. Wolber, D. Classen-Houben, O. Doblhoffe, D. Schuster, and A. Odermatt. Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11 beta-hydroxysteroid dehydrogenase type 2, J Steroid Biochem, 125(1-2):129-142, 2011.
Links:
[doi:10.1016/J.Jsbmb.2010.12.019]
[show BibTeX]
[show abstract]
x
@article{RN45,
author = {Kratschmar, D. V. and Vuorinen, A. and Da
Cunha, T. and Wolber, G. and
Classen-Houben, D. and Doblhoffe, O. and
Schuster, D. and Odermatt, A.},
title = {Characterization of activity and binding
mode of glycyrrhetinic acid derivatives
inhibiting 11 beta-hydroxysteroid
dehydrogenase type 2},
journal = {Journal of Steroid Biochemistry and
Molecular Biology},
volume = {125},
number = {1-2},
pages = {129-142},
note = {Sp. Iss. SI 784QX Times Cited:10 Cited
References Count:59},
abstract = {Modulation of intracellular
glucocorticoid availability is considered
as a promising strategy to treat
glucocorticoid-dependent diseases. 18
beta-Glycyrrhetinic acid (GA), the
biologically active triterpenoid
metabolite of glycyrrhizin, which is
contained in the roots and rhizomes of
licorice (Glycyrrhiza spp.), represents a
well-known but non-selective inhibitor of
11 beta-hydroxysteroid dehydrogenases (11
beta-HSDs). However, to assess the
physiological functions of the respective
enzymes and for potential therapeutic
applications selective inhibitors are
needed. In the present study, we applied
bioassays and 3D-structure modeling to
characterize nine 11 beta-HSD1 and fifteen
11 beta-HSD2 inhibiting GA derivatives.
Comparison of the GA derivatives in assays
using cell lysates revealed that
modifications at the 3-hydroxyl and/or the
carboxyl led to highly selective and
potent 11 beta-HSD2 inhibitors. The data
generated significantly extends our
knowledge on structure-activity
relationship of GA derivatives as 11
beta-HSD inhibitors. Using recombinant
enzymes we found also potent inhibition of
mouse 11 beta-HSD2, despite significant
species-specific differences. The selected
GA derivatives potently inhibited 11
beta-HSD2 in intact SW-620 colon cancer
cells, although the rank order of
inhibitory potential differed from that
obtained in cell lysates. The biological
activity of compounds was further
demonstrated in glucocorticoid receptor
(GR) transactivation assays in cells
coexpressing GR and 11 beta-HSD1 or 11
beta-HSD2. 3D-structure modeling provides
an explanation for the differences in the
selectivity and activity of the GA
derivatives investigated. The most potent
and selective 11 beta-HSD2 inhibitors
should prove useful as mechanistic tools
for further anti-inflammatory and
anti-cancer in vitro and in vivo studies.
Article from the Special issue on Targeted
Inhibitors. (C) 2011 Elsevier Ltd. All
rights reserved.},
keywords = {11 beta-hydroxysteroid dehydrogenase
glucocorticoid steroid metabolism
inhibitor glycyrrhetinic acid
pharmacophore 18-beta-glycyrrhetinic acid
cell-proliferation 11-beta-hsd1 inhibitors
selective inhibitors glucocorticoids
expression arthritis rat hypertension
cloning},
ISSN = {0960-0760},
DOI = {10.1016/J.Jsbmb.2010.12.019},
url = {Go to ISI://WOS:000292174400015
http://ac.els-cdn.com/S0960076011000057/1-s2.0-S0960076011000057-main.pdf?_tid= f070383a-4240-11e4-87eb-00000aab0f27&acdnat=1411380920_f9714622e17077fee892d66e6f45e49a},
year = {2011},
type = {Journal Article}
}
x
Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11 beta-hydroxysteroid dehydrogenase type 2
Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18 beta-Glycyrrhetinic acid (GA), the biologically active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs). However, to assess the physiological functions of the respective enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11 beta-HSD1 and fifteen 11 beta-HSD2 inhibiting GA derivatives. Comparison of the GA derivatives in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11 beta-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11 beta-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11 beta-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11 beta-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biological activity of compounds was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11 beta-HSD1 or 11 beta-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivatives investigated. The most potent and selective 11 beta-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.
S. M. Noha, A. G. Atanasov, D. Schuster, P. Markt, N. Fakhrudin, E. H. Heiss, O. Schrammel, J. M. Rollinger, H. Stuppner, V. M. Dirsch, and G. Wolber. Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques, Bioorg Med Chem Lett, 21(1):577-583, 2011.
Links:
[doi:10.1016/J.Bmcl.2010.10.051]
[show BibTeX]
[show abstract]
x
@article{RN53,
author = {Noha, S. M. and Atanasov, A. G. and
Schuster, D. and Markt, P. and Fakhrudin,
N. and Heiss, E. H. and Schrammel, O. and
Rollinger, J. M. and Stuppner, H. and
Dirsch, V. M. and Wolber, G.},
title = {Discovery of a novel IKK-β inhibitor by
ligand-based virtual screening
techniques},
journal = {Bioorganic & Medicinal Chemistry
Letters},
volume = {21},
number = {1},
pages = {577-583},
note = {697UN Times Cited:24 Cited References
Count:43},
abstract = {Various inflammatory stimuli that
activate the nuclear factor kappa B
(NF-kappa B) signaling pathway converge on
a serine/threonine kinase that displays a
key role in the activation of NF-kappa B:
the I kappa beta Bkinase beta (IKK-beta).
Therefore, IKK-beta is considered an
interesting target for combating
inflammation and cancer. In our study, we
developed a ligand-based pharmacophore
model for IKK-beta inhibitors. This model
was employed to virtually screen
commercial databases, giving a focused hit
list of candidates. Subsequently, we
scored by molecular shape to rank and
further prioritized virtual hits by
three-dimensional shape-based alignment.
One out of ten acquired and biologically
tested compounds showed inhibitory
activity in the low micromolar range on
IKK-beta enzymatic activity in vitro and
on NF-kappa B transactivation in intact
cells. Compound 8 (2-(1-adamantyl) ethyl
4-[(2,5-dihydroxyphenyl) methylamino]
benzoate) represents a novel chemical
class of IKK-beta inhibitors and shows
that the presented model is a valid
approach for identification and
development of new IKK-beta ligands. (C)
2010 Elsevier Ltd. All rights reserved.},
keywords = {i kappa b kinase beta ikk-beta virtual
screening pharmacophore shape-based
screening b kinase-beta nf-kappa-b
small-molecule inhibitor hit-to-lead
cancer-cells in-vitro inflammation design
potent model},
ISSN = {0960-894X},
DOI = {10.1016/J.Bmcl.2010.10.051},
url = {Go to ISI://WOS:000285544400122
http://ac.els-cdn.com/S0960894X1001512X/1-s2.0-S0960894X1001512X-main.pdf?_tid= e7822828-4240-11e4-9a26-00000aacb35e&acdnat=1411380905_15834d8aeb245e12d3dbba0e2b610014},
year = {2011},
type = {Journal Article}
}
x
Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques
Various inflammatory stimuli that activate the nuclear factor kappa B (NF-kappa B) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-kappa B: the I kappa beta Bkinase beta (IKK-beta). Therefore, IKK-beta is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-beta inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-beta enzymatic activity in vitro and on NF-kappa B transactivation in intact cells. Compound 8 (2-(1-adamantyl) ethyl 4-[(2,5-dihydroxyphenyl) methylamino] benzoate) represents a novel chemical class of IKK-beta inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-beta ligands. (C) 2010 Elsevier Ltd. All rights reserved.
P. H. Pfisterer, C. X. Shen, Z. Nikolovska-Coleska, L. Schyschka, D. Schuster, A. Rudy, G. Wolber, A. M. Vollmar, J. M. Rollinger, and H. Stuppner. In silico discovery of acylated flavonol monorhamnosides from Eriobotrya japonica as natural, small-molecular weight inhibitors of XIAP BIR3, Bioorg Med Chem, 19(2):1002-1009, 2011.
Links:
[doi:10.1016/J.Bmc.2010.10.046]
[show BibTeX]
[show abstract]
x
@article{RN49,
author = {Pfisterer, P. H. and Shen, C. X. and
Nikolovska-Coleska, Z. and Schyschka, L.
and Schuster, D. and Rudy, A. and Wolber,
G. and Vollmar, A. M. and Rollinger, J. M.
and Stuppner, H.},
title = {In silico discovery of acylated flavonol
monorhamnosides from Eriobotrya japonica
as natural, small-molecular weight
inhibitors of XIAP BIR3},
journal = {Bioorganic & Medicinal Chemistry},
volume = {19},
number = {2},
pages = {1002-1009},
note = {724QE Times Cited:0 Cited References
Count:53},
abstract = {Targeting the baculoviral inhibitor of
apoptosis proteins repeat (BIR) 3 of
X-linked inhibitor of apoptosis proteins
(XIAP) represents an innovative strategy
for the design of chemosensitizers.
Acylated flavonol monorhamnosides (AFMR)
from Eriobotrya japonica Lindl. (Rosaceae)
were virtually predicted as ligands of the
XIAP BIR3 domain by using a previously
generated pharmacophore model. From the
methanol leaf extract of E. japonica an
enriched mixture of AFMR was obtained
showing chemosensitizing potential in
combination with etoposide in
XIAP-overexpressing Jurkat cells. The
HPLC-SPE-NMR hyphenated technique
facilitated the structure elucidation of
three known and two new natural AFMR. The
main constituent and virtual hit,
kaempferol-3-O-alpha-L-(2 '',4
''-di-E-p-coumaroyl)-rhamnoside (3) was
isolated from the enriched fraction.
Applying a fluorescence polarization based
binding assay, 3 was identified as XIAP
BIR3 ligand with a dose-dependent affinity
(IC(50) 10.4 mu M). Further, 3 induced
apoptosis in XIAP-overexpressing Jurkat
cells and activated caspase-9 in
combination with etoposide. Docking
experiments revealed a major impact of the
coumaric acid and sugar moieties of 3 on
XIAP BIR3 binding, which was
experimentally confirmed. To conclude,
this study elucidates 3 as natural,
small-molecular weight XIAP BIR3 inhibitor
using a combination of in silico and
HPLC-SPE-NMR hyphenated techniques. (C)
2010 Published by Elsevier Ltd.},
keywords = {eriobotrya japonica molecular modeling
xiap bir3 chemosensitizer resistant
staphylococcus-aureus kaempferol induces
apoptosis structure-based design x-linked
inhibitor human glioma-cells
laurus-nobilis protein xiap combinatorial
chemistry mediated apoptosis
down-regulation},
ISSN = {0968-0896},
DOI = {10.1016/J.Bmc.2010.10.046},
url = {Go to ISI://WOS:000287590500031
http://ac.els-cdn.com/S0968089610009697/1-s2.0-S0968089610009697-main.pdf?_tid= e4826df4-4240-11e4-8d17-00000aab0f01&acdnat=1411380900_b468f81c63c984f71b8106b9f010a3a3},
year = {2011},
type = {Journal Article}
}
x
In silico discovery of acylated flavonol monorhamnosides from Eriobotrya japonica as natural, small-molecular weight inhibitors of XIAP BIR3
Targeting the baculoviral inhibitor of apoptosis proteins repeat (BIR) 3 of X-linked inhibitor of apoptosis proteins (XIAP) represents an innovative strategy for the design of chemosensitizers. Acylated flavonol monorhamnosides (AFMR) from Eriobotrya japonica Lindl. (Rosaceae) were virtually predicted as ligands of the XIAP BIR3 domain by using a previously generated pharmacophore model. From the methanol leaf extract of E. japonica an enriched mixture of AFMR was obtained showing chemosensitizing potential in combination with etoposide in XIAP-overexpressing Jurkat cells. The HPLC-SPE-NMR hyphenated technique facilitated the structure elucidation of three known and two new natural AFMR. The main constituent and virtual hit, kaempferol-3-O-alpha-L-(2 '',4 ''-di-E-p-coumaroyl)-rhamnoside (3) was isolated from the enriched fraction. Applying a fluorescence polarization based binding assay, 3 was identified as XIAP BIR3 ligand with a dose-dependent affinity (IC(50) 10.4 mu M). Further, 3 induced apoptosis in XIAP-overexpressing Jurkat cells and activated caspase-9 in combination with etoposide. Docking experiments revealed a major impact of the coumaric acid and sugar moieties of 3 on XIAP BIR3 binding, which was experimentally confirmed. To conclude, this study elucidates 3 as natural, small-molecular weight XIAP BIR3 inhibitor using a combination of in silico and HPLC-SPE-NMR hyphenated techniques. (C) 2010 Published by Elsevier Ltd.
A. Schafer, A. Wellner, M. Strauss, G. Wolber, and R. Gust. Development of 2,3,5-triaryl-1h-pyrroles as Estrogen receptor α selective ligands, ChemMedChem, 6(11):2055-2062, 2011.
Links:
[doi:10.1002/Cmdc.201100283]
[show BibTeX]
[show abstract]
x
@article{RN40,
author = {Schafer, A. and Wellner, A. and Strauss,
M. and Wolber, G. and Gust, R.},
title = {Development of 2,3,5-triaryl-1h-pyrroles
as Estrogen receptor α selective
ligands},
journal = {Chemmedchem},
volume = {6},
number = {11},
pages = {2055-2062},
note = {853HN Times Cited:3 Cited References
Count:25},
abstract = {1-Alkyl-2,3,5-triaryl-1H-pyrroles (for
which alkyl=methyl, ethyl, n-propyl, or
2-methylpropyl) were tested for stability,
estrogen receptor (ER) binding, and
inhibition of tumor cell growth. These
pyrroles (type B) showed higher stability
in aqueous solution than their
1,2,4-triaryl-1H-pyrrole congeners (type A
pyrroles), exclusive ER alpha binding (no
ER beta interaction), and a hormonal
profile of partial agonists at ER alpha.
The most potent compound,
1-(2-methylpropyl)-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole(5d),
was less active than the lead structure
1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole
(PPT) in MCF-7 cells stably transfected
with the plasmid ERE(wtc)luc (MCF-7/2a),
but more potent in U2-OS/alpha cells.
Furthermore, 5d showed weak antiestrogenic
properties (IC(50)= 310 nM). An additional
propyl chain at C4 decreased the stability
and pharmacological effects.},
keywords = {autoxidation cytotoxicity drug design
hormones nitrogen heterocycles cancer
cell-line biological evaluation binding
mode pharmacophores substituents
expression complexes agonists pattern
protein},
ISSN = {1860-7179},
DOI = {10.1002/Cmdc.201100283},
url = {Go to ISI://WOS:000297416900016
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201100283/abstract
http://onlinelibrary.wiley.com/store/10.1002/cmdc.201100283/asset/2055_ftp.pdf?v= 1&t=jdvm62xr&s=0a1c716ec030a5bbd99ce1333ff10b1162aab97b},
year = {2011},
type = {Journal Article}
}
x
Development of 2,3,5-triaryl-1h-pyrroles as Estrogen receptor α selective ligands
1-Alkyl-2,3,5-triaryl-1H-pyrroles (for which alkyl=methyl, ethyl, n-propyl, or 2-methylpropyl) were tested for stability, estrogen receptor (ER) binding, and inhibition of tumor cell growth. These pyrroles (type B) showed higher stability in aqueous solution than their 1,2,4-triaryl-1H-pyrrole congeners (type A pyrroles), exclusive ER alpha binding (no ER beta interaction), and a hormonal profile of partial agonists at ER alpha. The most potent compound, 1-(2-methylpropyl)-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole(5d), was less active than the lead structure 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) in MCF-7 cells stably transfected with the plasmid ERE(wtc)luc (MCF-7/2a), but more potent in U2-OS/alpha cells. Furthermore, 5d showed weak antiestrogenic properties (IC(50)= 310 nM). An additional propyl chain at C4 decreased the stability and pharmacological effects.
D. Schuster, D. Kowalik, J. Kirchmair, C. Laggner, P. Markt, C. Aebischer-Gumy, F. Strohle, G. Moller, G. Wolber, T. Wilckens, T. Langer, A. Odermatt, and J. Adamski. Identification of chemically diverse, novel inhibitors of 17 beta-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening, J Steroid Biochem, 125(1-2):148-161, 2011.
Links:
[doi:10.1016/J.Jsbmb.2011.01.016]
[show BibTeX]
[show abstract]
x
@article{RN46,
author = {Schuster, D. and Kowalik, D. and
Kirchmair, J. and Laggner, C. and Markt,
P. and Aebischer-Gumy, C. and Strohle, F.
and Moller, G. and Wolber, G. and
Wilckens, T. and Langer, T. and Odermatt,
A. and Adamski, J.},
title = {Identification of chemically diverse,
novel inhibitors of 17 beta-hydroxysteroid
dehydrogenase type 3 and 5 by
pharmacophore-based virtual screening},
journal = {Journal of Steroid Biochemistry and
Molecular Biology},
volume = {125},
number = {1-2},
pages = {148-161},
note = {Sp. Iss. SI 784QX Times Cited:9 Cited
References Count:73},
abstract = {17 beta-Hydroxysteroid dehydrogenase type
3 and 5 (17 beta-HSD3 and 17 beta-HSD5)
catalyze testosterone biosynthesis and
thereby constitute therapeutic targets for
androgen-related diseases or
endocrine-disrupting chemicals. As a fast
and efficient tool to identify potential
ligands for 17 beta HSD3/5, ligand-and
structure-based pharmacophore models for
both enzymes were developed. The models
were evaluated first by in silico
screening of commercial compound databases
and further experimentally validated by
enzymatic efficacy tests of selected
virtual hits. Among the 35 tested
compounds, 11 novel inhibitors with
distinct chemical scaffolds, e.g.
sulfonamides and triazoles, and with
different selectivity properties were
discovered. Thereby, we provide several
potential starting points for further 17
beta-HSD3 and 17 beta-HSD5 inhibitor
development. Article from the Special
issue on Targeted Inhibitors. (C) 2011
Elsevier Ltd. All rights reserved.},
keywords = {pharmacophore screening inhibitor
development steroid-dependent disease
androgens estrogens
prostaglandin-f-synthase nonsteroidal
antiinflammatory drugs in-silico
pharmacology keto reductase akr1c3
11-beta-hydroxysteroid dehydrogenases
20-alpha-hydroxysteroid dehydrogenase
4-hydroxyphenyl ketones biochemical
evaluation crystal-structures discovery},
ISSN = {0960-0760},
DOI = {10.1016/J.Jsbmb.2011.01.016},
url = {Go to ISI://WOS:000292174400017
http://ac.els-cdn.com/S096007601100029X/1-s2.0-S096007601100029X-main.pdf?_tid= f36a6740-4240-11e4-8c6b-00000aacb362&acdnat=1411380925_0833b0aacfad662a3b491df135cdb746},
year = {2011},
type = {Journal Article}
}
x
Identification of chemically diverse, novel inhibitors of 17 beta-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening
17 beta-Hydroxysteroid dehydrogenase type 3 and 5 (17 beta-HSD3 and 17 beta-HSD5) catalyze testosterone biosynthesis and thereby constitute therapeutic targets for androgen-related diseases or endocrine-disrupting chemicals. As a fast and efficient tool to identify potential ligands for 17 beta HSD3/5, ligand-and structure-based pharmacophore models for both enzymes were developed. The models were evaluated first by in silico screening of commercial compound databases and further experimentally validated by enzymatic efficacy tests of selected virtual hits. Among the 35 tested compounds, 11 novel inhibitors with distinct chemical scaffolds, e.g. sulfonamides and triazoles, and with different selectivity properties were discovered. Thereby, we provide several potential starting points for further 17 beta-HSD3 and 17 beta-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.
D. Schuster, P. Markt, U. Grienke, J. Mihaly-Bison, M. Binder, S. M. Noha, J. M. Rollinger, H. Stuppner, V. N. Bochkov, and G. Wolber. Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation, Bioorg Med Chem, 19(23):7168-7180, 2011.
Links:
[doi:10.1016/J.Bmc.2011.09.056]
[show BibTeX]
[show abstract]
x
@article{RN38,
author = {Schuster, D. and Markt, P. and Grienke,
U. and Mihaly-Bison, J. and Binder, M. and
Noha, S. M. and Rollinger, J. M. and
Stuppner, H. and Bochkov, V. N. and
Wolber, G.},
title = {Pharmacophore-based discovery of FXR
agonists. Part I: Model development and
experimental validation},
journal = {Bioorganic & Medicinal Chemistry},
volume = {19},
number = {23},
pages = {7168-7180},
note = {844MW Times Cited:8 Cited References
Count:49},
abstract = {The farnesoid X receptor (FXR) is
involved in glucose and lipid metabolism
regulation, which makes it an attractive
target for the metabolic syndrome,
dyslipidemia, atherosclerosis, and type 2
diabetes. In order to find novel FXR
agonists, a structure-based pharmacophore
model collection was developed and
theoretically evaluated against virtual
databases including the ChEMBL database.
The most suitable models were used to
screen the National Cancer Institute (NCI)
database. Biological evaluation of virtual
hits led to the discovery of a novel FXR
agonist with a piperazine scaffold
(compound 19) that shows comparable
activity as the endogenous FXR agonist
chenodeoxycholic acid (CDCA, compound 2).
(C) 2011 Elsevier Ltd. All rights
reserved.},
keywords = {farnesoid x receptor molecular modeling
virtual screening lead identification fxr
agonist farnesoid-x-receptor bile-acid
receptor nuclear receptor drug discovery
potent identification antagonist
activation database analogs},
ISSN = {0968-0896},
DOI = {10.1016/J.Bmc.2011.09.056},
url = {Go to ISI://WOS:000296752300023
http://ac.els-cdn.com/S0968089611007917/1-s2.0-S0968089611007917-main.pdf?_tid= d9c96cf0-4240-11e4-b1af-00000aacb362&acdnat=1411380882_821a3ff30b0a83526fc8e74ae85a2ab4},
year = {2011},
type = {Journal Article}
}
x
Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation
The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was developed and theoretically evaluated against virtual databases including the ChEMBL database. The most suitable models were used to screen the National Cancer Institute (NCI) database. Biological evaluation of virtual hits led to the discovery of a novel FXR agonist with a piperazine scaffold (compound 19) that shows comparable activity as the endogenous FXR agonist chenodeoxycholic acid (CDCA, compound 2). (C) 2011 Elsevier Ltd. All rights reserved.
B. Waltenberger, D. Schuster, S. Paramapojn, W. Gritsanapan, G. Wolber, J. M. Rollinger, and H. Stuppner. Predicting cyclooxygenase inhibition by three-dimensional pharmacophoric profiling. Part II: Identification of enzyme inhibitors from Prasaplai, a Thai traditional medicine, Phytomedicine, 18(2-3):119-133, 2011.
Links:
[doi:10.1016/J.Phymed.2010.08.002]
[show BibTeX]
[show abstract]
x
@article{RN48,
author = {Waltenberger, B. and Schuster, D. and
Paramapojn, S. and Gritsanapan, W. and
Wolber, G. and Rollinger, J. M. and
Stuppner, H.},
title = {Predicting cyclooxygenase inhibition by
three-dimensional pharmacophoric
profiling. Part II: Identification of
enzyme inhibitors from Prasaplai, a Thai
traditional medicine},
journal = {Phytomedicine},
volume = {18},
number = {2-3},
pages = {119-133},
note = {726ZU Times Cited:0 Cited References
Count:56},
abstract = {Prasaplai is a medicinal plant mixture
that is used in Thailand to treat primary
dysmenorrhea, which is characterized by
painful uterine contractility caused by a
significant increase of prostaglandin
release. Cyclooxygenase (COX) represents a
key enzyme in the formation of
prostaglandins. Former studies revealed
that extracts of Prasaplai inhibit COX-1
and COX-2. In this study, a comprehensive
literature survey for known constituents
of Prasaplai was performed. A
multiconformational 3D database was
created comprising 683 molecules. Virtual
parallel screening using six validated
pharmacophore models for COX inhibitors
was performed resulting in a hit list of
166 compounds. 46 Prasaplai components
with already determined COX activity were
used for the external validation of this
set of COX pharmacophore models. 57% of
these components were classified correctly
by the pharmacophore models. These
findings confirm that the virtual approach
provides a helpful tool (i) to unravel
which molecular compounds might be
responsible for the COX-inhibitory
activity of Prasaplai and (ii) for the
fast identification of novel COX
inhibitors. (C) 2010 Elsevier GmbH. All
rights reserved.},
keywords = {prasaplai traditional medicine of
thailand natural products cyclooxygenase
pharmacophore virtual screening cancer
chemopreventive agents in-silico
pharmacology drug discovery
natural-products allium-sativum cox-2
inhibitors constituents seeds analogs
acid},
ISSN = {0944-7113},
DOI = {10.1016/J.Phymed.2010.08.002},
url = {Go to ISI://WOS:000287767800005
http://ac.els-cdn.com/S0944711310002564/1-s2.0-S0944711310002564-main.pdf?_tid= d764b1cc-4240-11e4-8566-00000aacb361&acdnat=1411380878_04ee0e1144e9c8d4d34a03cb1fb4d185},
year = {2011},
type = {Journal Article}
}
x
Predicting cyclooxygenase inhibition by three-dimensional pharmacophoric profiling. Part II: Identification of enzyme inhibitors from Prasaplai, a Thai traditional medicine
Prasaplai is a medicinal plant mixture that is used in Thailand to treat primary dysmenorrhea, which is characterized by painful uterine contractility caused by a significant increase of prostaglandin release. Cyclooxygenase (COX) represents a key enzyme in the formation of prostaglandins. Former studies revealed that extracts of Prasaplai inhibit COX-1 and COX-2. In this study, a comprehensive literature survey for known constituents of Prasaplai was performed. A multiconformational 3D database was created comprising 683 molecules. Virtual parallel screening using six validated pharmacophore models for COX inhibitors was performed resulting in a hit list of 166 compounds. 46 Prasaplai components with already determined COX activity were used for the external validation of this set of COX pharmacophore models. 57% of these components were classified correctly by the pharmacophore models. These findings confirm that the virtual approach provides a helpful tool (i) to unravel which molecular compounds might be responsible for the COX-inhibitory activity of Prasaplai and (ii) for the fast identification of novel COX inhibitors. (C) 2010 Elsevier GmbH. All rights reserved.
B. Waltenberger, K. Wiechmann, J. Bauer, P. Markt, S. M. Noha, G. Wolber, J. M. Rollinger, O. Werz, D. Schuster, and H. Stuppner. Pharmacophore modeling and virtual screening for novel acidic inhibitors of microsomal prostaglandin E-2 synthase-1 (mPGES-1), J Med Chem, 54(9):3163-3174, 2011.
Links:
[doi:10.1021/Jm101309g]
[show BibTeX]
[show abstract]
x
@article{RN44,
author = {Waltenberger, B. and Wiechmann, K. and
Bauer, J. and Markt, P. and Noha, S. M.
and Wolber, G. and Rollinger, J. M. and
Werz, O. and Schuster, D. and Stuppner,
H.},
title = {Pharmacophore modeling and virtual
screening for novel acidic inhibitors of
microsomal prostaglandin E-2 synthase-1
(mPGES-1)},
journal = {Journal of Medicinal Chemistry},
volume = {54},
number = {9},
pages = {3163-3174},
note = {757YY Times Cited:17 Cited References
Count:30},
abstract = {Microsomal prostaglandin E-2 synthase-1
(mPGES-1) catalyzes prostaglandin E-2
formation and is considered as a potential
anti-inflammatory pharmacological target.
To identify novel chemical scaffolds
active on this enzyme, two pharmacophore
models for acidic mPGES-1 inhibitors were
developed and theoretically validated
using information on mPGES-1 inhibitors
from literature. The models were used to
screen chemical databases supplied from
the National Cancer Institute (NCI) and
the Specs. Out of 29 compounds selected
for biological evaluation, nine chemically
diverse compounds caused
concentration-dependent inhibition of
mPGES-1 activity in a cell-free assay with
IC50 values between 0.4 and 7.9 mu M,
respectively. Further pharmacological
characterization revealed that also
5-lipoxygenase (5-LO) was inhibited by
most of these active compounds in
cell-free and cell-based assays with IC50
values in the low micromolar range.
Together, nine novel chemical scaffolds
inhibiting mPGES-1 are presented that may
possess anti-inflammatory properties based
on the interference with eicosanoid
biosynthesis.},
keywords = {therapeutic target 5-lipoxygenase
inflammation 3d-qsar cancer cells},
ISSN = {0022-2623},
DOI = {10.1021/Jm101309g},
url = {Go to ISI://WOS:000290126800003
http://pubs.acs.org/doi/pdfplus/10.1021/jm101309g},
year = {2011},
type = {Journal Article}
}
x
Pharmacophore modeling and virtual screening for novel acidic inhibitors of microsomal prostaglandin E-2 synthase-1 (mPGES-1)
Microsomal prostaglandin E-2 synthase-1 (mPGES-1) catalyzes prostaglandin E-2 formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC50 values between 0.4 and 7.9 mu M, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC50 values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGES-1 are presented that may possess anti-inflammatory properties based on the interference with eicosanoid biosynthesis.
N. Fakhrudin, A. Ladurner, A. G. Atanasov, E. H. Heiss, L. Baumgartner, P. Markt, D. Schuster, E. P. Ellmerer, G. Wolber, J. M. Rollinger, H. Stuppner, and V. M. Dirsch. Computer-aided discovery, validation, and mechanistic characterization of novel neolignan activators of peroxisome proliferator-activated receptor γ, Mol Pharmacol, 77(4):559-566, 2010.
Links:
[doi:10.1124/mol.109.062141]
[show BibTeX]
[show abstract]
x
@article{RN146,
author = {Fakhrudin, Nanang and Ladurner, Angela
and Atanasov, Atanas G. and Heiss, Elke H.
and Baumgartner, Lisa and Markt, Patrick
and Schuster, Daniela and Ellmerer, Ernst
P. and Wolber, Gerhard and Rollinger,
Judith M. and Stuppner, Hermann and
Dirsch, Verena M.},
title = {Computer-aided discovery, validation, and
mechanistic characterization of novel
neolignan activators of peroxisome
proliferator-activated receptor γ},
journal = {Molecular Pharmacology},
volume = {77},
number = {4},
pages = {559-566},
abstract = {Peroxisome proliferator-activated
receptor gamma (PPARγ) agonists are used
for the treatment of type 2 diabetes and
metabolic syndrome. However, the currently
used PPARγ agonists display serious side
effects, which has led to a great interest
in the discovery of novel ligands with
favorable properties. The aim of our study
was to identify new PPARγ agonists by a
PPARγ pharmacophore–based virtual
screening of 3D natural product libraries.
This in silico approach led to the
identification of several neolignans
predicted to bind the receptor ligand
binding domain (LBD). To confirm this
prediction, the neolignans dieugenol,
tetrahydrodieugenol, and magnolol were
isolated from the respective natural
source or synthesized and subsequently
tested for PPARγ receptor binding. The
neolignans bound to the PPARγ LBD with
EC50 values in the nanomolar range,
exhibiting a binding pattern highly
similar to the clinically used agonist
pioglitazone. In intact cells, dieugenol
and tetrahydrodieugenol selectively
activated human PPARγ-mediated, but not
human PPARα- or -β/δ-mediated
luciferase reporter expression, with a
pattern suggesting partial PPARγ agonism.
The coactivator recruitment study also
demonstrated partial agonism of the tested
neolignans. Dieugenol,
tetrahydrodieugenol, and magnolol but not
the structurally related eugenol induced
3T3-L1 preadipocyte differentiation,
confirming effectiveness in a cell model
with endogenous PPARγ expression. In
conclusion, we identified neolignans as
novel ligands for PPARγ, which exhibited
interesting activation profiles,
recommending them as potential
pharmaceutical leads or dietary
supplements.},
DOI = {10.1124/mol.109.062141},
url = {http://molpharm.aspetjournals.org/content/77/4/559.abstract
http://molpharm.aspetjournals.org/content/77/4/559.full.pdf},
year = {2010},
type = {Journal Article}
}
x
Computer-aided discovery, validation, and mechanistic characterization of novel neolignan activators of peroxisome proliferator-activated receptor γ
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used for the treatment of type 2 diabetes and metabolic syndrome. However, the currently used PPARγ agonists display serious side effects, which has led to a great interest in the discovery of novel ligands with favorable properties. The aim of our study was to identify new PPARγ agonists by a PPARγ pharmacophore–based virtual screening of 3D natural product libraries. This in silico approach led to the identification of several neolignans predicted to bind the receptor ligand binding domain (LBD). To confirm this prediction, the neolignans dieugenol, tetrahydrodieugenol, and magnolol were isolated from the respective natural source or synthesized and subsequently tested for PPARγ receptor binding. The neolignans bound to the PPARγ LBD with EC50 values in the nanomolar range, exhibiting a binding pattern highly similar to the clinically used agonist pioglitazone. In intact cells, dieugenol and tetrahydrodieugenol selectively activated human PPARγ-mediated, but not human PPARα- or -β/δ-mediated luciferase reporter expression, with a pattern suggesting partial PPARγ agonism. The coactivator recruitment study also demonstrated partial agonism of the tested neolignans. Dieugenol, tetrahydrodieugenol, and magnolol but not the structurally related eugenol induced 3T3-L1 preadipocyte differentiation, confirming effectiveness in a cell model with endogenous PPARγ expression. In conclusion, we identified neolignans as novel ligands for PPARγ, which exhibited interesting activation profiles, recommending them as potential pharmaceutical leads or dietary supplements.
M. Goebel, G. Wolber, P. Markt, B. Staels, T. Unger, U. Kintscher, and R. Gust. Characterization of new PPARγ agonists: Benzimidazole derivatives-importance of positions 5 and 6, and computational studies on the binding mode, Bioorg Med Chem, 18(16):5885-5895, 2010.
Links:
[doi:10.1016/J.Bmc.2010.06.102]
[show BibTeX]
[show abstract]
x
@article{RN59,
author = {Goebel, M. and Wolber, G. and Markt, P.
and Staels, B. and Unger, T. and
Kintscher, U. and Gust, R.},
title = {Characterization of new PPARγ agonists:
Benzimidazole derivatives-importance of
positions 5 and 6, and computational
studies on the binding mode},
journal = {Bioorganic & Medicinal Chemistry},
volume = {18},
number = {16},
pages = {5885-5895},
note = {635OD Times Cited:11 Cited References
Count:38},
abstract = {In this and previous studies we
investigated the importance of partial
structures of Telmisartan on PPAR gamma
activation. The biphenyl-4-ylmethyl moiety
at N1 and residues at C2 of the central
benzimidazole were identified to be
essential for receptor activation and
potency of receptor binding. Now we
focused our attention on positions 5 and 6
of the central benzimidazole and
introduced bromine (3b-5/6, 3c),
phenylcarbonyl (3d-5/6), hydroxy(phenyl)
methyl (3g-5/6), hydroxymethyl (3h-5/6)
and formyl (3i) groups. The selection of
these moieties was inspired by the
structure of Losartan and its metabolite
EXP3179. In order to increase the
hydrophobicity of the central part of the
molecule, the benzimidazole was exchanged
by a naphtho[2,3-d] imidazole (5). The
compounds 3a-3i and 5 were tested in a
differentiation assay using 3T3-L1
preadipocytes and a luciferase assay using
COS-7 cells, transiently transfected with
pGal4-hPPAR gamma DEF, pGal5-TK-pGL3 and
pRL-CMV, as established models for the
assessment of cellular PPAR gamma
activation. An enhanced effect on PPAR
gamma activation could be observed if
lipophilic moieties are introduced in
these positions. 4
'-[(2-Propyl-1H-naphtho[2,3-d]
imidazol-1-yl) methyl]
biphenyl-2-carboxylic acid (5) was
identified as the most potent compound
with an EC(50) of 0.26 mu M and the
profile of a full agonist. Together with
compounds of the former structure-activity
relationship study (position 2-substituted
benzimidazole derivatives 4a-4j), the
binding mode of Telmisartan and its
derivatives have been analyzed in 3D
pharmacophore-driven docking experiments.
(C) 2010 Elsevier Ltd. All rights
reserved.},
keywords = {benzimidazole derivatives partial agonism
selective ppar gamma modulators
structure-activity relationship molecular
modeling proliferator-activated receptors
molecular recognition biological
evaluation fatty-acids alpha ligands
pharmacophores metabolites discovery},
ISSN = {0968-0896},
DOI = {10.1016/J.Bmc.2010.06.102},
url = {Go to ISI://WOS:000280664100011
http://ac.els-cdn.com/S0968089610006309/1-s2.0-S0968089610006309-main.pdf?_tid= 1dbbb09e-4241-11e4-974e-00000aacb361&acdnat=1411380996_1a144cf8b6d634f437abc795aa808c95},
year = {2010},
type = {Journal Article}
}
x
Characterization of new PPARγ agonists: Benzimidazole derivatives-importance of positions 5 and 6, and computational studies on the binding mode
In this and previous studies we investigated the importance of partial structures of Telmisartan on PPAR gamma activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl) methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d] imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPAR gamma DEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPAR gamma activation. An enhanced effect on PPAR gamma activation could be observed if lipophilic moieties are introduced in these positions. 4 '-[(2-Propyl-1H-naphtho[2,3-d] imidazol-1-yl) methyl] biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC(50) of 0.26 mu M and the profile of a full agonist. Together with compounds of the former structure-activity relationship study (position 2-substituted benzimidazole derivatives 4a-4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments. (C) 2010 Elsevier Ltd. All rights reserved.
U. Grienke, M. Schmidtke, J. Kirchmair, K. Pfarr, P. Wutzler, R. Durrwald, G. Wolber, K. R. Liedl, H. Stuppner, and J. M. Rollinger. Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia Katsumadai, J Med Chem, 53(2):778-786, 2010.
Links:
[doi:10.1021/Jm901440f]
[show BibTeX]
[show abstract]
x
@article{RN73,
author = {Grienke, U. and Schmidtke, M. and
Kirchmair, J. and Pfarr, K. and Wutzler,
P. and Durrwald, R. and Wolber, G. and
Liedl, K. R. and Stuppner, H. and
Rollinger, J. M.},
title = {Antiviral potential and molecular insight
into neuraminidase inhibiting
diarylheptanoids from Alpinia Katsumadai},
journal = {Journal of Medicinal Chemistry},
volume = {53},
number = {2},
pages = {778-786},
note = {544PX Times Cited:35 Cited References
Count:53},
abstract = {At present, neuraminidase (NA) inhibitors
are the mainstay of pharmacological
strategies to fight against global
pandemic influenza. In the search for new
antiviral drug leads from nature, the seed
extract of Alpinia katsumadai has been
phytochemically investigated. Among the
six isolated constituents, four
diarylheptanoids showed in vitro NA
inhibitory activities in low micromolar
ranges against human influenza virus
A/PR/8/34 of subtype H(1)N(1). The most
promising constituent, katsumadain A (4;
IC(50) = 1.05 +/- 0.42 mu M), also
inhibited the NA of Four H(1)N(1) swine
influenza viruses, with IC(50) values
between 0.9 and 1.64 mu M, and showed
antiviral effects in plaque reduction
assays. Considering the flexible loop
regions of NA, extensive molecular
dynamics (MD) simulations were performed
to study the putative binding mechanism of
the T-shaped diarylheptanoid 4. Docking
results showed well-established
interactions between the protein and the
core of this novel NA-inhibiting natural
scaffold, excellent surface
complementarity to the simulated binding
pocket, and concordance with
experimentally derived SAR data.},
keywords = {influenza-a-viruses oseltamivir-resistant
influenza amantadine resistance adamantane
resistance drug design emergence dynamics
germany h1n1 surveillance},
ISSN = {0022-2623},
DOI = {10.1021/Jm901440f},
url = {Go to ISI://WOS:000273672100024
http://pubs.acs.org/doi/pdfplus/10.1021/jm901440f},
year = {2010},
type = {Journal Article}
}
x
Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia Katsumadai
At present, neuraminidase (NA) inhibitors are the mainstay of pharmacological strategies to fight against global pandemic influenza. In the search for new antiviral drug leads from nature, the seed extract of Alpinia katsumadai has been phytochemically investigated. Among the six isolated constituents, four diarylheptanoids showed in vitro NA inhibitory activities in low micromolar ranges against human influenza virus A/PR/8/34 of subtype H(1)N(1). The most promising constituent, katsumadain A (4; IC(50) = 1.05 +/- 0.42 mu M), also inhibited the NA of Four H(1)N(1) swine influenza viruses, with IC(50) values between 0.9 and 1.64 mu M, and showed antiviral effects in plaque reduction assays. Considering the flexible loop regions of NA, extensive molecular dynamics (MD) simulations were performed to study the putative binding mechanism of the T-shaped diarylheptanoid 4. Docking results showed well-established interactions between the protein and the core of this novel NA-inhibiting natural scaffold, excellent surface complementarity to the simulated binding pocket, and concordance with experimentally derived SAR data.
L. G. Nashev, D. Schuster, C. Laggner, S. Sodha, T. Langer, G. Wolber, and A. Odermatt. The UV-filter benzophenone-1 inhibits 17 beta-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals, Biochem Pharmacol, 79(8):1189-1199, 2010.
Links:
[doi:10.1016/J.Bcp.2009.12.005]
[show BibTeX]
[show abstract]
x
@article{RN70,
author = {Nashev, L. G. and Schuster, D. and
Laggner, C. and Sodha, S. and Langer, T.
and Wolber, G. and Odermatt, A.},
title = {The UV-filter benzophenone-1 inhibits 17
beta-hydroxysteroid dehydrogenase type 3:
Virtual screening as a strategy to
identify potential endocrine disrupting
chemicals},
journal = {Biochemical Pharmacology},
volume = {79},
number = {8},
pages = {1189-1199},
note = {566RT Times Cited:13 Cited References
Count:61},
abstract = {The prevalence of male reproductive
disorders and testicular cancer is
steadily increasing. Because the exposure
to chemicals disrupting natural hormone
action has been associated with these
diseases, it is important to identify
endocrine disrupting chemicals (EDCs) and
their targets of action. Here, a
3D-structural database that can be applied
for virtual screening approaches to
facilitate the identification of EDCs was
constructed. The database was screened
using pharmacophores of 17
beta-hydroxysteroid dehydrogenase type 3
(17 beta-HSD3), which catalyzes the last
step of testosterone synthesis in
testicular Leydig cells and plays an
essential role during male sexual
development. Among other chemicals,
benzophenone (BP) UV-filters were
predicted as potential 17 beta-HSD3
inhibitors. Biological analyses revealed
(2,4-dihydroxyphenyl)-phenylmethanone
(also known as benzophenone-1, BP-1) as an
inhibitor of human 17 beta-HSD3 (IC50 1.05
mu M). BP-1 also efficiently blocked
conversion of androstenedione to
testosterone by mouse and rat 17 beta-HSD3
in whole-organ enzyme assays. Moreover,
BP-I antagonized the
testosterone-dependent activation of
androgen receptors (IC50 5.7 mu M),
suggesting synergistic anti-androgenic
effects of BP-1 by preventing testosterone
formation and blocking receptor
activation. In addition, analyses of
several commonly used UV-filters on
estrogen- and androgen-metabolizing 17
beta-HSD enzymes revealed 3-benzylidene
camphor (3-BC) and 4-methylbenzylidene
camphor (4-MBC) as low micromolar 17
beta-HSD2 inhibitors. In conclusion,
screening of virtual chemical structure
libraries can facilitate the
identification of compounds interfering
with hormone action. The potential
disruption of 17 beta-HSD enzyme function
by the UV-filters BP-1, 3-BC and 4-MBC
requires further investigation and should
be considered for safety assessment of
these chemicals. (C) 2009 Elsevier Inc.
All rights reserved.},
keywords = {17 beta-hydroxysteroid dehydrogenase
androgen testosterone endocrine disruptor
pharmacophore virtual screening uv-filter
body topical application developmental
toxicity estrogenic activity surface
waters swiss lakes derivatives phthalate
fish identification sunscreens},
ISSN = {0006-2952},
DOI = {10.1016/J.Bcp.2009.12.005},
url = {Go to ISI://WOS:000275391400014
http://ac.els-cdn.com/S0006295209010624/1-s2.0-S0006295209010624-main.pdf?_tid= 1318166e-4241-11e4-ab41-00000aacb35e&acdnat=1411380978_cdb785e0811ed886426510660287dd66},
year = {2010},
type = {Journal Article}
}
x
The UV-filter benzophenone-1 inhibits 17 beta-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals
The prevalence of male reproductive disorders and testicular cancer is steadily increasing. Because the exposure to chemicals disrupting natural hormone action has been associated with these diseases, it is important to identify endocrine disrupting chemicals (EDCs) and their targets of action. Here, a 3D-structural database that can be applied for virtual screening approaches to facilitate the identification of EDCs was constructed. The database was screened using pharmacophores of 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3), which catalyzes the last step of testosterone synthesis in testicular Leydig cells and plays an essential role during male sexual development. Among other chemicals, benzophenone (BP) UV-filters were predicted as potential 17 beta-HSD3 inhibitors. Biological analyses revealed (2,4-dihydroxyphenyl)-phenylmethanone (also known as benzophenone-1, BP-1) as an inhibitor of human 17 beta-HSD3 (IC50 1.05 mu M). BP-1 also efficiently blocked conversion of androstenedione to testosterone by mouse and rat 17 beta-HSD3 in whole-organ enzyme assays. Moreover, BP-I antagonized the testosterone-dependent activation of androgen receptors (IC50 5.7 mu M), suggesting synergistic anti-androgenic effects of BP-1 by preventing testosterone formation and blocking receptor activation. In addition, analyses of several commonly used UV-filters on estrogen- and androgen-metabolizing 17 beta-HSD enzymes revealed 3-benzylidene camphor (3-BC) and 4-methylbenzylidene camphor (4-MBC) as low micromolar 17 beta-HSD2 inhibitors. In conclusion, screening of virtual chemical structure libraries can facilitate the identification of compounds interfering with hormone action. The potential disruption of 17 beta-HSD enzyme function by the UV-filters BP-1, 3-BC and 4-MBC requires further investigation and should be considered for safety assessment of these chemicals. (C) 2009 Elsevier Inc. All rights reserved.
P. H. Pfisterer, G. Wolber, T. Efferth, J. M. Rollinger, and H. Stuppner. Natural products in structure-assisted design of molecular cancer therapeutics, Curr Pharm Design, 16(15):1718-1741, 2010.
Links:
[doi:10.2174/138161210791164027]
[show BibTeX]
[show abstract]
x
@article{RN68,
author = {Pfisterer, P. H. and Wolber, G. and
Efferth, T. and Rollinger, J. M. and
Stuppner, H.},
title = {Natural products in structure-assisted
design of molecular cancer therapeutics},
journal = {Current Pharmaceutical Design},
volume = {16},
number = {15},
pages = {1718-1741},
note = {589DO Times Cited:8 Cited References
Count:243},
abstract = {Since the late 1990's, novel insights
into molecular biology and carcinogenesis
enabled the rational design of
mechanismbased anticancer therapeutics.
The large number of natural product
(NP)-derived drugs currently under
clinical evaluation and the recent
approval of temsirolimus (Torisel (R)) as
a first mTOR protein kinase inhibitor
indicate that NPs have to be considered
not only as a seminal source of cytotoxic,
but also as a source of molecularly
targeted agents. Whereas molecular
modeling is well established as an
important and successful method to
discover and rationalize bioactivities in
medicinal chemistry research, its
application has proven to be also a
powerful tool in the field of NPs. This
review highlights the impact of
computer-assisted approaches on NPs as
molecularly targeted anticancer drugs.
Examples of applications are provided
focusing on innovative targets such as
protein kinases, tumour vasculature,
epigenetic modulators, heat shock protein
(Hsp) 90, and direct apoptosis
enhancers.},
keywords = {natural product phytochemicals cancer
drug discovery in silico techniques
molecular modeling virtual screening
docking histone deacetylase inhibitors
x-linked inhibitor tyrosine kinase
inhibitors growth-factor receptor
microtubule-stabilizing agents traditional
chinese medicine containing hydroxamic
acids constrained smac mimetics
structure-based discovery apoptotic bcl-2
proteins},
ISSN = {1381-6128},
DOI = {10.2174/138161210791164027},
url = {Go to ISI://WOS:000277126000007
http://www.eurekaselect.com/71574/article
https://www.eurekaselect.com/71574/article},
year = {2010},
type = {Journal Article}
}
x
Natural products in structure-assisted design of molecular cancer therapeutics
Since the late 1990's, novel insights into molecular biology and carcinogenesis enabled the rational design of mechanismbased anticancer therapeutics. The large number of natural product (NP)-derived drugs currently under clinical evaluation and the recent approval of temsirolimus (Torisel (R)) as a first mTOR protein kinase inhibitor indicate that NPs have to be considered not only as a seminal source of cytotoxic, but also as a source of molecularly targeted agents. Whereas molecular modeling is well established as an important and successful method to discover and rationalize bioactivities in medicinal chemistry research, its application has proven to be also a powerful tool in the field of NPs. This review highlights the impact of computer-assisted approaches on NPs as molecularly targeted anticancer drugs. Examples of applications are provided focusing on innovative targets such as protein kinases, tumour vasculature, epigenetic modulators, heat shock protein (Hsp) 90, and direct apoptosis enhancers.
J. M. Rollinger, D. V. Kratschmar, D. Schuster, P. H. Pfisterer, C. Gumy, E. M. Aubry, S. Brandstotter, H. Stuppner, G. Wolber, and A. Odermatt. 11β-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya Japonica revealed by bioactivity-guided isolation and computational approaches, Bioorg Med Chem, 18(4):1507-1515, 2010.
Links:
[doi:10.1016/J.Bmc.2010.01.010]
[show BibTeX]
[show abstract]
x
@article{RN72,
author = {Rollinger, J. M. and Kratschmar, D. V.
and Schuster, D. and Pfisterer, P. H. and
Gumy, C. and Aubry, E. M. and
Brandstotter, S. and Stuppner, H. and
Wolber, G. and Odermatt, A.},
title = {11β-Hydroxysteroid dehydrogenase 1
inhibiting constituents from Eriobotrya
Japonica revealed by bioactivity-guided
isolation and computational approaches},
journal = {Bioorganic & Medicinal Chemistry},
volume = {18},
number = {4},
pages = {1507-1515},
note = {554HG Times Cited:12 Cited References
Count:55},
abstract = {The inhibition of 11 beta-hydroxysteroid
dehydrogenase 1 (11 beta-HSD1), which
catalyzes the conversion of inactive
11-ketoglucocorticoids to active 11
beta-hydroxyglucocorticoids, emerged as
promising strategy to treat symptoms of
the metabolic syndrome, including obesity
and type 2 diabetes. In this study the
leaves of the anti-diabetic medicinal
plant loquat (Eriobotrya japonica) were
phytochemically investigated following
hints from a pharmacophore-based virtual
screening and a bioactivity-guided
approach. Determination of the 11
beta-HSD1 and 11 beta-HSD2 inhibitory
activities in cell lysates revealed
triterpenes from the ursane type as
selective, low micro-molar inhibitors of
11 beta-HSD1, that is, corosolic acid (1),
3-epicorosolic acid methyl ester (4),
2-alpha hydroxy-3-oxo urs-12-en-28-oic
acid (6), tormentic acid methyl ester (8),
and ursolic acid (9). Importantly, a
mixture of loquat constituents with
moderate activities displayed a pronounced
additive effect. By means of molecular
modeling studies and the identification of
the 11 beta-HSD1-inhibiting
11-keto-ursolic acid (17) and
3-acetyl-11-keto-ursolic acid (18) a
structure -activity relationship was
deduced for this group of pentacyclic
triterpenes. The mechanism of action
elucidated in the present work together
with the previously determined
pharmacological activities provides these
natural products with an astonishing
multi-targeted anti-diabetic profile. (C)
2010 Elsevier Ltd. All rights reserved.},
keywords = {eriobotrya japonica 11 beta-hsd1 diabetes
glucocorticoid receptor metabolic syndrome
occurring pentacyclic triterpenes
corosolic acid folium-eriobotryae
metabolic syndrome diabetes-mellitus
type-1 inhibitors protein leaves
pharmacophores glycosides},
ISSN = {0968-0896},
DOI = {10.1016/J.Bmc.2010.01.010},
url = {Go to ISI://WOS:000274425500016
http://ac.els-cdn.com/S0968089610000295/1-s2.0-S0968089610000295-main.pdf?_tid= 07b1dcce-4241-11e4-a26d-00000aab0f6c&acdnat=1411380959_65bcb9a54c995606feea5afea87bb4fd},
year = {2010},
type = {Journal Article}
}
x
11β-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya Japonica revealed by bioactivity-guided isolation and computational approaches
The inhibition of 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1), which catalyzes the conversion of inactive 11-ketoglucocorticoids to active 11 beta-hydroxyglucocorticoids, emerged as promising strategy to treat symptoms of the metabolic syndrome, including obesity and type 2 diabetes. In this study the leaves of the anti-diabetic medicinal plant loquat (Eriobotrya japonica) were phytochemically investigated following hints from a pharmacophore-based virtual screening and a bioactivity-guided approach. Determination of the 11 beta-HSD1 and 11 beta-HSD2 inhibitory activities in cell lysates revealed triterpenes from the ursane type as selective, low micro-molar inhibitors of 11 beta-HSD1, that is, corosolic acid (1), 3-epicorosolic acid methyl ester (4), 2-alpha hydroxy-3-oxo urs-12-en-28-oic acid (6), tormentic acid methyl ester (8), and ursolic acid (9). Importantly, a mixture of loquat constituents with moderate activities displayed a pronounced additive effect. By means of molecular modeling studies and the identification of the 11 beta-HSD1-inhibiting 11-keto-ursolic acid (17) and 3-acetyl-11-keto-ursolic acid (18) a structure -activity relationship was deduced for this group of pentacyclic triterpenes. The mechanism of action elucidated in the present work together with the previously determined pharmacological activities provides these natural products with an astonishing multi-targeted anti-diabetic profile. (C) 2010 Elsevier Ltd. All rights reserved.
R. Rubbiani, I. Kitanovic, H. Alborzinia, S. Can, A. Kitanovic, L. A. Onambele, M. Stefanopoulou, Y. Geldmacher, W. S. Sheldrick, G. Wolber, A. Prokop, S. Wolfl, and I. Ottt. Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties, J Med Chem, 53(24):8608-8618, 2010.
Links:
[doi:10.1021/Jm100801e]
[show BibTeX]
[show abstract]
x
@article{RN54,
author = {Rubbiani, R. and Kitanovic, I. and
Alborzinia, H. and Can, S. and Kitanovic,
A. and Onambele, L. A. and Stefanopoulou,
M. and Geldmacher, Y. and Sheldrick, W. S.
and Wolber, G. and Prokop, A. and Wolfl,
S. and Ottt, I.},
title = {Benzimidazol-2-ylidene gold(I) complexes
are thioredoxin reductase inhibitors with
multiple antitumor properties},
journal = {Journal of Medicinal Chemistry},
volume = {53},
number = {24},
pages = {8608-8618},
note = {693ZQ Times Cited:78 Cited References
Count:58},
abstract = {Gold(I) complexes such as auranofin have
been used for decades to treat symptoms of
rheumatoid arthritis and have also
demonstrated a considerable potential as
new anticancer drugs. The enzyme
thioredoxin reductase (TrxR) is considered
as the most relevant molecular target for
these species. The here investigated
gold(I) complexes with benzimidazole
derived N-heterocyclic carbene (NHC)
ligands 1a-4a represent a promising class
of gold coordination compounds with a good
stability against the thiol glutathione.
TrxR was selectively inhibited by 1a-4a in
comparison to the closely related enzyme
glutathione reductase, and all complexes
triggered significant antiproliferative
effects in cultured tumor cells. More
detailed studies on a selected complex
(2a) revealed a distinct pharmacodynamic
profile including the high increase of
reactive oxygen species formation,
apoptosis induction, strong effects on
cellular metabolism (related to cell
surface properties, respiration, and
glycolysis), inhibition of mitochondrial
respiration and activity against resistant
cell lines.},
keywords = {n-heterocyclic carbene antimicrobial
activity phosphine-ligands metal-complexes
cancer-cells mitochondria pharmacophores
ruthenium(ii) cytotoxicity chemistry},
ISSN = {0022-2623},
DOI = {10.1021/Jm100801e},
url = {Go to ISI://WOS:000285264300014
http://pubs.acs.org/doi/pdfplus/10.1021/jm100801e},
year = {2010},
type = {Journal Article}
}
x
Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties
Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands 1a-4a represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by 1a-4a in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex (2a) revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.
D. Schuster, L. Kern, D. P. Hristozov, L. Terfloth, B. Bienfait, C. Laggner, J. Kirchmair, U. Grienke, G. Wolber, T. Langer, H. Stuppner, J. Gasteiger, and J. M. Rollinger. Applications of integrated data mining methods to explore natural product space for Acetylcholinesterase inhibitors, Combinatorial Chemistry & High Throughput Screening, 13(1):54-66, 2010.
Links:
[doi:10.2174/138620710790218212]
[show BibTeX]
[show abstract]
x
@article{RN75,
author = {Schuster, D. and Kern, L. and Hristozov,
D. P. and Terfloth, L. and Bienfait, B.
and Laggner, C. and Kirchmair, J. and
Grienke, U. and Wolber, G. and Langer, T.
and Stuppner, H. and Gasteiger, J. and
Rollinger, J. M.},
title = {Applications of integrated data mining
methods to explore natural product space
for Acetylcholinesterase inhibitors},
journal = {Combinatorial Chemistry & High Throughput
Screening},
volume = {13},
number = {1},
pages = {54-66},
note = {549DE Times Cited:5 Cited References
Count:54},
abstract = {Nature, especially the plant kingdom, is
a rich source for novel bioactive
compounds that can be used as lead
compounds for drug development. In order
to exploit this resource, the two neural
network-based virtual screening techniques
novelty detection with self-organizing
maps (SOMs) and counterpropagation neural
network were evaluated as tools for
efficient lead structure discovery. As
application scenario, significant
descriptors for acetylcholinesterase
(AChE) inhibitors were determined and used
for model building, theoretical model
validation, and virtual screening.
Top-ranked virtual hits from both
approaches were docked into the AChE
binding site to approve the initial hits.
Finally, in vitro testing of selected
compounds led to the identification of
forsythoside A and (+)-sesamolin as novel
AChE inhibitors.},
keywords = {natural products drug discovery
acetylcholinesterase virtual screening
counterpropagation network spinne novelty
detection active-site gorge
torpedo-californica acetylcholinesterase
in-silico pharmacology novelty detection
neural-networks drug discovery
counterpropagation networks
infrared-spectra protein binding},
ISSN = {1386-2073},
DOI = {10.2174/138620710790218212},
url = {Go to ISI://WOS:000274021800007},
year = {2010},
type = {Journal Article}
}
x
Applications of integrated data mining methods to explore natural product space for Acetylcholinesterase inhibitors
Nature, especially the plant kingdom, is a rich source for novel bioactive compounds that can be used as lead compounds for drug development. In order to exploit this resource, the two neural network-based virtual screening techniques novelty detection with self-organizing maps (SOMs) and counterpropagation neural network were evaluated as tools for efficient lead structure discovery. As application scenario, significant descriptors for acetylcholinesterase (AChE) inhibitors were determined and used for model building, theoretical model validation, and virtual screening. Top-ranked virtual hits from both approaches were docked into the AChE binding site to approve the initial hits. Finally, in vitro testing of selected compounds led to the identification of forsythoside A and (+)-sesamolin as novel AChE inhibitors.
D. Schuster, M. Spetea, M. Music, S. Rief, M. Fink, J. Kirchmair, J. Schutz, G. Wolber, T. Langer, H. Stuppner, H. Schmidhammer, and J. M. Rollinger. Morphinans and isoquinolines: Acetylcholinesterase inhibition, pharmacophore modeling, and interaction with opioid receptors, Bioorg Med Chem, 18(14):5071-5080, 2010.
Links:
[doi:10.1016/J.Bmc.2010.05.071]
[show BibTeX]
[show abstract]
x
@article{RN64,
author = {Schuster, D. and Spetea, M. and Music, M.
and Rief, S. and Fink, M. and Kirchmair,
J. and Schutz, J. and Wolber, G. and
Langer, T. and Stuppner, H. and
Schmidhammer, H. and Rollinger, J. M.},
title = {Morphinans and isoquinolines:
Acetylcholinesterase inhibition,
pharmacophore modeling, and interaction
with opioid receptors},
journal = {Bioorganic & Medicinal Chemistry},
volume = {18},
number = {14},
pages = {5071-5080},
note = {623MN Times Cited:12 Cited References
Count:42},
abstract = {Following indications from
pharmacophore-based virtual screening of
natural product databases, morphinan and
isoquinoline compounds were tested in
vitro for acetylcholinesterase (AChE)
inhibition. After the first screen, active
and inactive compounds were used to build
a ligand-based pharmacophore model in
order to prioritize compounds for
biological testing. Among the virtual hits
tested, the enrichment of actives was
significantly higher than in a random
selection of test compounds. The most
active compounds were biochemically tested
for their activity on mu, delta, and kappa
opioid receptors. (C) 2010 Elsevier Ltd.
All rights reserved.},
keywords = {morphinans acetylcholinesterase
inhibition opioid receptor pharmacophore
modeling lead structure discovery
in-silico pharmacology biological
evaluation drug discovery natural-products
highly potent 14-alkoxymorphinans agonist
derivatives binding},
ISSN = {0968-0896},
DOI = {10.1016/J.Bmc.2010.05.071},
url = {Go to ISI://WOS:000279744700025
http://ac.els-cdn.com/S096808961000502X/1-s2.0-S096808961000502X-main.pdf?_tid= 16953092-4241-11e4-9a26-00000aacb35e&acdnat=1411380984_f0779c4eeef7c816ebcd45393f5b7194},
year = {2010},
type = {Journal Article}
}
x
Morphinans and isoquinolines: Acetylcholinesterase inhibition, pharmacophore modeling, and interaction with opioid receptors
Following indications from pharmacophore-based virtual screening of natural product databases, morphinan and isoquinoline compounds were tested in vitro for acetylcholinesterase (AChE) inhibition. After the first screen, active and inactive compounds were used to build a ligand-based pharmacophore model in order to prioritize compounds for biological testing. Among the virtual hits tested, the enrichment of actives was significantly higher than in a random selection of test compounds. The most active compounds were biochemically tested for their activity on mu, delta, and kappa opioid receptors. (C) 2010 Elsevier Ltd. All rights reserved.
D. Schuster, B. Waltenberger, J. Kirchmair, S. Distinto, P. Markt, H. Stuppner, J. M. Rollinger, and G. Wolber. Predicting Cyclooxygenase inhibition by three-dimensional pharmacophoric profiling. Part I: model generation, validation, and applicability in ethnopharmacology, Mol Inf, 29(1-2):75-86, 2010.
Links:
[doi:10.1002/Minf.200900071]
[show BibTeX]
[show abstract]
x
@article{RN74,
author = {Schuster, D. and Waltenberger, B. and
Kirchmair, J. and Distinto, S. and Markt,
P. and Stuppner, H. and Rollinger, J. M.
and Wolber, G.},
title = {Predicting Cyclooxygenase inhibition by
three-dimensional pharmacophoric
profiling. Part I: model generation,
validation, and applicability in
ethnopharmacology},
journal = {Molecular Informatics},
volume = {29},
number = {1-2},
pages = {75-86},
note = {573AA Times Cited:9 Cited References
Count:62},
abstract = {3D pharmacophore modeling has evolved as
an established and state-of-the-art method
for performing in-silico predictions of
biological activity. Using one single
model is limited to single binding modes,
while the combination of several models
bears a broader application scope. We
demonstrate the generation of a complete
and predictive 3D model set for
cyclooxygenase 1 and 2 inhibitors, along
with a selection and validation protocol
optimized for parallel virtual screening.
This model set was applied to explain the
cyclooxygenase activity of an
ethnopharmacologically known mixture of
natural products, the Thai traditional
medicine "Prasaplai". Results show that
rationalizing natural product activity by
modern in-silico approaches is promising
and can be tremendously useful in the
identification of the mechanisms of action
for known biological effects of complex
herbal remedies.},
keywords = {molecular modeling parallel screening
cyclooxygenase inhibitors
ethnopharmacology prasaplai medicinal
chemistry molecular modeling prostaglandin
h-2 synthase high-throughput docking drug
discovery cox-2 inhibitors silico
pharmacology natural-products ppar ligands
chemistry optimization constituents},
ISSN = {1868-1743},
DOI = {10.1002/Minf.200900071},
url = {Go to ISI://WOS:000275879300008
http://onlinelibrary.wiley.com/store/10.1002/minf.200900071/asset/75_ftp.pdf?v= 1&t=i0dnol2q&s=71943a78fb1d037012a4867a156bf738e3a4cf5c},
year = {2010},
type = {Journal Article}
}
x
Predicting Cyclooxygenase inhibition by three-dimensional pharmacophoric profiling. Part I: model generation, validation, and applicability in ethnopharmacology
3D pharmacophore modeling has evolved as an established and state-of-the-art method for performing in-silico predictions of biological activity. Using one single model is limited to single binding modes, while the combination of several models bears a broader application scope. We demonstrate the generation of a complete and predictive 3D model set for cyclooxygenase 1 and 2 inhibitors, along with a selection and validation protocol optimized for parallel virtual screening. This model set was applied to explain the cyclooxygenase activity of an ethnopharmacologically known mixture of natural products, the Thai traditional medicine "Prasaplai". Results show that rationalizing natural product activity by modern in-silico approaches is promising and can be tremendously useful in the identification of the mechanisms of action for known biological effects of complex herbal remedies.
D. Schuster, and G. Wolber. Identification of bioactive natural products by pharmacophore-based virtual screening, Curr Pharm Design, 16(15):1666-1681, 2010.
Links:
[doi:10.2174/138161210791164072]
[show BibTeX]
[show abstract]
x
@article{RN69,
author = {Schuster, D. and Wolber, G.},
title = {Identification of bioactive natural
products by pharmacophore-based virtual
screening},
journal = {Current Pharmaceutical Design},
volume = {16},
number = {15},
pages = {1666-1681},
note = {589DO Times Cited:16 Cited References
Count:105},
abstract = {Natural products have been exposed to a
long selection process to interact with
biological targets and are therefore a
valuable source for ideas for novel
chemical entities in drug development.
However, the process to determine
activities of natural products is mainly
based on serendipity, and can thus become
time- and cost-intensive. In this review
we present strategies on how modern
in-silico molecular modeling techniques
can be used to make this process more
efficient and discuss how to discover and
optimize drug candidates inspired by
nature. Focusing on 3D pharmacophore
modeling techniques, we provide an
overview of virtual screening and modeling
methods, review available in silico
databases as sources for chemical
structures of natural products, discuss
techniques for biological activity
profiling, and summarize recent success
stories for the combination of in-silico
approaches and pharmacognosy.},
keywords = {pharmacophore modeling virtual screening
natural products natural product databases
parallel screening 11-beta-hydroxysteroid
dehydrogenase type-1 relationship
3d/4d-qsar analyses bound ligand
conformations rhinovirus coat protein
high-throughput docking in-silico
pharmacology drug discovery medicinal
chemistry historical-perspective compound
libraries},
ISSN = {1381-6128},
DOI = {10.2174/138161210791164072},
url = {Go to ISI://WOS:000277126000003
http://www.eurekaselect.com/71570/article},
year = {2010},
type = {Journal Article}
}
x
Identification of bioactive natural products by pharmacophore-based virtual screening
Natural products have been exposed to a long selection process to interact with biological targets and are therefore a valuable source for ideas for novel chemical entities in drug development. However, the process to determine activities of natural products is mainly based on serendipity, and can thus become time- and cost-intensive. In this review we present strategies on how modern in-silico molecular modeling techniques can be used to make this process more efficient and discuss how to discover and optimize drug candidates inspired by nature. Focusing on 3D pharmacophore modeling techniques, we provide an overview of virtual screening and modeling methods, review available in silico databases as sources for chemical structures of natural products, discuss techniques for biological activity profiling, and summarize recent success stories for the combination of in-silico approaches and pharmacognosy.
A. M. Scutaru, M. Wenzel, H. Scheffler, G. Wolber, and R. Gust. Optimization of the N-lost drugs Melphalan and Bendamustine: Synthesis and cytotoxicity of a new set of dendrimer-drug conjugates as tumor therapeutic agents, Bioconjug Chem, 21(10):1728-1743, 2010.
Links:
[doi:10.1021/Bc900453f]
[show BibTeX]
[show abstract]
x
@article{RN56,
author = {Scutaru, A. M. and Wenzel, M. and
Scheffler, H. and Wolber, G. and Gust,
R.},
title = {Optimization of the N-lost drugs
Melphalan and Bendamustine: Synthesis and
cytotoxicity of a new set of
dendrimer-drug conjugates as tumor
therapeutic agents},
journal = {Bioconjugate Chemistry},
volume = {21},
number = {10},
pages = {1728-1743},
note = {666FZ Times Cited:3 Cited References
Count:47},
abstract = {Bendamustine and melphalan are very
promising alkylating drugs with
applicability in the treatment of various
tumoral diseases, e.g., chronic
lymphocytic leukemia (CLL) or breast
cancer. However, numerous adverse effects
limited their use. Therefore,
1,3,5-tris(3-aminopropyl)benzene (G0) and
its G1 analogue
3,5-bis(3-aminopropyl)-N-(3-{3,5-bis[3-{3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide
were selected to design cytostatic
drug-dendrimer conjugates to achieve tumor
cell accumulation by endocytosis as
already demonstrated for platinum
complexes. The dendrimers act as carriers
and an N-(2-hydroxyethyl)maleimide spacer
between drug and carrier should guarantee
a selective release of the cytostatics in
the tumor cells. The resulting
cytotoxicity was determined in vitro using
the human MCF-7 and MDA-MB-231 breast
cancer cell lines. It was demonstrated
that melphalan caused cytotoxic effects
depending on its free amino group (Boc
protection strongly decreased the
activity) but independent of a derivation
of the carboxylic group (dendrimers and
spacer binding). Esterification of
bendamustine with the
N-(2-hydroxyethyl)maleimide spacer
strongly increased the hydrolytic
stability of the N-lost moiety, so
antiproliferative effects were yet
observed in vitro.},
keywords = {human serum-albumin in-vitro efficacy
cancer-chemotherapy protein-binding
breast-cancer cell-lines delivery
macromolecules chlorambucil hydrolysis},
ISSN = {1043-1802},
DOI = {10.1021/Bc900453f},
url = {Go to ISI://WOS:000283101000004
http://pubs.acs.org/doi/pdfplus/10.1021/bc900453f},
year = {2010},
type = {Journal Article}
}
x
Optimization of the N-lost drugs Melphalan and Bendamustine: Synthesis and cytotoxicity of a new set of dendrimer-drug conjugates as tumor therapeutic agents
Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3-aminopropyl)-N-(3-{3,5-bis[3-{3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB-231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2-hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro.
T. Seidel, G. Ibis, F. Bendix, and G. Wolber. Strategies for 3D pharmacophore-based virtual screening, Drug Discovery Today: Technologies, 7(4):e221-e228, 2010.
Links:
[doi:10.1016/j.ddtec.2010.11.004]
[show BibTeX]
[show abstract]
x
@article{RN149,
author = {Seidel, Thomas and Ibis, Gökhan and
Bendix, Fabian and Wolber, Gerhard},
title = {Strategies for 3D pharmacophore-based
virtual screening},
journal = {Drug Discovery Today: Technologies},
volume = {7},
number = {4},
pages = {e221-e228},
abstract = {3D pharmacophore-based techniques have
become one of the most important
approaches for the fast and accurate
virtual screening of databases with
millions of compounds. The success of 3D
pharmacophores is largely based on their
intuitive interpretation and creation, but
the virtual screening with such
three-dimensional geometric models still
poses a considerable algorithmic and
conceptual challenge. Most current
implementations favor fast screening speed
at the detriment of accuracy. This review
describes the general strategies and
algorithms employed for 3D pharmacophore
searching by some current pharmacophore
modeling platforms and will highlight
their differences.},
ISSN = {1740-6749},
DOI = {10.1016/j.ddtec.2010.11.004},
url = {http://www.sciencedirect.com/science/article/pii/S1740674910000375
http://ac.els-cdn.com/S1740674910000375/1-s2.0-S1740674910000375-main.pdf?_tid= a44c90c2-4338-11e4-b35e-00000aab0f26&acdnat=1411487308_5e2a9c8b80c22ea886bffb40225bf767},
year = {2010},
type = {Journal Article}
}
x
Strategies for 3D pharmacophore-based virtual screening
3D pharmacophore-based techniques have become one of the most important approaches for the fast and accurate virtual screening of databases with millions of compounds. The success of 3D pharmacophores is largely based on their intuitive interpretation and creation, but the virtual screening with such three-dimensional geometric models still poses a considerable algorithmic and conceptual challenge. Most current implementations favor fast screening speed at the detriment of accuracy. This review describes the general strategies and algorithms employed for 3D pharmacophore searching by some current pharmacophore modeling platforms and will highlight their differences.
G. M. Spitzer, M. Heiss, M. Mangold, P. Mark, J. Kirchmair, G. Wolber, and K. R. Liedl. One concept, three implementations of 3D pharmacophore-based virtual screening: Distinct coverage of chemical search space, J Chem Inf Model, 50(7):1241-1247, 2010.
Links:
[doi:10.1021/Ci100136b]
[show BibTeX]
[show abstract]
x
@article{RN65,
author = {Spitzer, G. M. and Heiss, M. and Mangold,
M. and Mark, P. and Kirchmair, J. and
Wolber, G. and Liedl, K. R.},
title = {One concept, three implementations of 3D
pharmacophore-based virtual screening:
Distinct coverage of chemical search
space},
journal = {Journal of Chemical Information and
Modeling},
volume = {50},
number = {7},
pages = {1241-1247},
note = {629GL Times Cited:17 Cited References
Count:36},
abstract = {Feature-based pharmacophore modeling is a
well-established concept to support early
stage drug discovery, where large virtual
databases are filtered for potential drug
candidates. The concept is implemented in
popular molecular modeling software,
including Catalyst, Phase, and MOE. With
these software tools we performed a
comparative virtual screening campaign on
HSP90 and FXIa, taken from the 'maximum
unbiased validation' data set. Despite the
straightforward concept that
pharmacophores are based on, we observed
an unexpectedly high degree of variation
among the hit lists obtained. By
harmonizing the pharmacophore feature
definitions of the investigated
approaches, the exclusion volume sphere
settings, and the screening parameters, we
have derived a rationale for the observed
differences, providing insight on the
strengths and weaknesses of these
algorithms. Application of more than one
of these software tools in parallel will
result in a widened coverage of chemical
space. This is not only rooted in the
dissimilarity of feature definitions but
also in different algorithmic search
strategies.},
keywords = {3-d pharmacophores molecular docking
hsp90 inhibitors factor xia database
protein discovery design phase sets},
ISSN = {1549-9596},
DOI = {10.1021/Ci100136b},
url = {Go to ISI://WOS:000280183200005
http://pubs.acs.org/doi/pdfplus/10.1021/ci100136b},
year = {2010},
type = {Journal Article}
}
x
One concept, three implementations of 3D pharmacophore-based virtual screening: Distinct coverage of chemical search space
Feature-based pharmacophore modeling is a well-established concept to support early stage drug discovery, where large virtual databases are filtered for potential drug candidates. The concept is implemented in popular molecular modeling software, including Catalyst, Phase, and MOE. With these software tools we performed a comparative virtual screening campaign on HSP90 and FXIa, taken from the 'maximum unbiased validation' data set. Despite the straightforward concept that pharmacophores are based on, we observed an unexpectedly high degree of variation among the hit lists obtained. By harmonizing the pharmacophore feature definitions of the investigated approaches, the exclusion volume sphere settings, and the screening parameters, we have derived a rationale for the observed differences, providing insight on the strengths and weaknesses of these algorithms. Application of more than one of these software tools in parallel will result in a widened coverage of chemical space. This is not only rooted in the dissimilarity of feature definitions but also in different algorithmic search strategies.
G. Wolber. 3D pharmacophore elucidation and virtual screening, Drug Discovery Today: Technologies, 7(4):e203-e204, 2010.
Links:
[doi:10.1016/j.ddtec.2010.12.004]
[show BibTeX]
x
@article{RN148,
author = {Wolber, Gerhard},
title = {3D pharmacophore elucidation and virtual
screening},
journal = {Drug Discovery Today: Technologies},
volume = {7},
number = {4},
pages = {e203-e204},
ISSN = {1740-6749},
DOI = {10.1016/j.ddtec.2010.12.004},
url = {http://www.sciencedirect.com/science/article/pii/S1740674910000594
http://ac.els-cdn.com/S1740674910000594/1-s2.0-S1740674910000594-main.pdf?_tid= 9d9770c6-4338-11e4-8e98-00000aab0f26&acdnat=1411487297_6c73913aac983d10bbaefbbd42d854c2},
year = {2010},
type = {Journal Article}
}
D. Classen-Houben, D. Schuster, T. Da Cunha, A. Odermatt, G. Wolber, U. Jordis, and B. Kueenburg. Selective inhibition of 11β-hydroxysteroid dehydrogenase 1 by 18 alpha-glycyrrhetinic acid but not 18 beta-glycyrrhetinic acid, J Steroid Biochem, 113(3-5):248-252, 2009.
Links:
[doi:10.1016/J.Jsbmb.2009.01.009]
[show BibTeX]
[show abstract]
x
@article{RN80,
author = {Classen-Houben, D. and Schuster, D. and
Da Cunha, T. and Odermatt, A. and Wolber,
G. and Jordis, U. and Kueenburg, B.},
title = {Selective inhibition of
11β-hydroxysteroid dehydrogenase 1 by 18
alpha-glycyrrhetinic acid but not 18
beta-glycyrrhetinic acid},
journal = {Journal of Steroid Biochemistry and
Molecular Biology},
volume = {113},
number = {3-5},
pages = {248-252},
note = {425WE Times Cited:19 Cited References
Count:34},
abstract = {Elevated cortisol concentrations have
been associated with metabolic diseases
such as diabetes type 2 and obesity. 11
beta-hydroxysteroid dehydrogenase (11
beta-HSD) type 1, catalyzing the
conversion of inactive
11-ketoglucocorticoids into their active
Ilp-hydroxy forms, plays an important role
in the regulation of cortisol levels
within specific tissues. The selective
inhibition of 11 beta-HSD1 is currently
considered as promising therapeutic
strategy for the treatment of metabolic
diseases. In recent years, natural
compound-derived drug design has gained
considerable interest. 18
beta-glycyrrhetinic acid (GA), a
metabolite of the natural product
glycyrrhizin, is not selective and
inhibits both 11 beta-HSD1 and 11
beta-HSD2. Here, we compare the biological
activity of 18 beta-GA and its
diastereomer 18 alpha-GA against the two
enzymes in lysates of transfected HEK-293
cells and show that 18 alpha-GA
selectively inhibits 11 beta-HSD1 but not
11 beta-HSD2. This is in contrast to 18
beta-GA, which preferentially inhibits 11
beta-HSD2. Using a pharmacophore model
based on the crystal structure of the
GA-derivative carbenoxolone in complex
with human 11 beta-HSD1, we provide an
explanation for the differences in the
activities of 18 alpha-GA and 18 beta-GA.
This model will be used to design novel
selective derivatives of GA. (C) 2009
Elsevier Ltd. All rights reserved.},
keywords = {glycyrrhetinic acid 11beta-hydroxysteroid
dehydrogenase 11 beta-hsd glucocorticoid
inhibitor ligandscout pharmacophore model
metabolic syndrome glycyrrhetic acid
type-1 derivatives obesity pharmacophores
variability sensitivity metabolism
reductase receptor},
ISSN = {0960-0760},
DOI = {10.1016/J.Jsbmb.2009.01.009},
url = {Go to ISI://WOS:000264667700015
http://ac.els-cdn.com/S0960076009000235/1-s2.0-S0960076009000235-main.pdf?_tid= 3fb59e94-4241-11e4-9940-00000aacb35e&acdnat=1411381053_e5218dc0338bb5180ca2156369c587b7},
year = {2009},
type = {Journal Article}
}
x
Selective inhibition of 11β-hydroxysteroid dehydrogenase 1 by 18 alpha-glycyrrhetinic acid but not 18 beta-glycyrrhetinic acid
Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active Ilp-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11 beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18 beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11 beta-HSD1 and 11 beta-HSD2. Here, we compare the biological activity of 18 beta-GA and its diastereomer 18 alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18 alpha-GA selectively inhibits 11 beta-HSD1 but not 11 beta-HSD2. This is in contrast to 18 beta-GA, which preferentially inhibits 11 beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11 beta-HSD1, we provide an explanation for the differences in the activities of 18 alpha-GA and 18 beta-GA. This model will be used to design novel selective derivatives of GA. (C) 2009 Elsevier Ltd. All rights reserved.
J. Kirchmair, S. Distinto, P. Markt, D. Schuster, G. M. Spitzer, K. R. Liedl, and G. Wolber. How to optimize shape-based virtual screening: Choosing the right query and including chemical information, J Chem Inf Model, 49(3):678-692, 2009.
Links:
[doi:10.1021/Ci8004226]
[show BibTeX]
[show abstract]
x
@article{RN79,
author = {Kirchmair, J. and Distinto, S. and Markt,
P. and Schuster, D. and Spitzer, G. M. and
Liedl, K. R. and Wolber, G.},
title = {How to optimize shape-based virtual
screening: Choosing the right query and
including chemical information},
journal = {Journal of Chemical Information and
Modeling},
volume = {49},
number = {3},
pages = {678-692},
note = {423YT Times Cited:66 Cited References
Count:56},
abstract = {Shape-based molecular similarity
approaches have been established as
important and popular virtual screening
techniques. Recent applications have shown
successful screening campaigns using
different parameters and query selection.
It is common sense that pure volume
overlap scoring (or "shape-based
screening") under-represents chemical or
pharmacophoric information of a molecule.
Using the "Directory of Useful Decoys"
(DUD) as a benchmark set, we
systematically evaluate how (i) the choice
of query conformations, (ii) the selection
of the active compound to be used as a
query structure, and (iii) the inclusion
of chemical information (i.e., the
pharmacophoric properties of the query
molecule) affect screening performance.
Varying these parameters bears remarkable
potential for improvements and delivers
the best screening performance reported
using these tools so far. From these
insights, guidelines on how to reach
optimum performance during virtual
screening are developed.},
keywords = {high-throughput docking hiv entry
inhibitors molecular shape pharmacophore
models drug discovery data fusion
similarity recognition performance
efficiency},
ISSN = {1549-9596},
DOI = {10.1021/Ci8004226},
url = {Go to ISI://WOS:000264533400016
http://pubs.acs.org/doi/pdfplus/10.1021/ci8004226},
year = {2009},
type = {Journal Article}
}
x
How to optimize shape-based virtual screening: Choosing the right query and including chemical information
Shape-based molecular similarity approaches have been established as important and popular virtual screening techniques. Recent applications have shown successful screening campaigns using different parameters and query selection. It is common sense that pure volume overlap scoring (or "shape-based screening") under-represents chemical or pharmacophoric information of a molecule. Using the "Directory of Useful Decoys" (DUD) as a benchmark set, we systematically evaluate how (i) the choice of query conformations, (ii) the selection of the active compound to be used as a query structure, and (iii) the inclusion of chemical information (i.e., the pharmacophoric properties of the query molecule) affect screening performance. Varying these parameters bears remarkable potential for improvements and delivers the best screening performance reported using these tools so far. From these insights, guidelines on how to reach optimum performance during virtual screening are developed.
P. Markt, C. Feldmann, J. M. Rollinger, S. Raduner, D. Schuster, J. Kirchmair, S. Distinto, G. M. Spitzer, G. Wolber, C. Laggner, K. H. Altmann, T. Langer, and J. Gertsch. Discovery of novel CB2 receptor ligands by a pharmacophore-based virtual screening workflow, J Med Chem, 52(2):369-378, 2009.
Links:
[doi:10.1021/Jm801044g]
[show BibTeX]
[show abstract]
x
@article{RN82,
author = {Markt, P. and Feldmann, C. and Rollinger,
J. M. and Raduner, S. and Schuster, D. and
Kirchmair, J. and Distinto, S. and
Spitzer, G. M. and Wolber, G. and Laggner,
C. and Altmann, K. H. and Langer, T. and
Gertsch, J.},
title = {Discovery of novel CB2 receptor ligands
by a pharmacophore-based virtual screening
workflow},
journal = {Journal of Medicinal Chemistry},
volume = {52},
number = {2},
pages = {369-378},
note = {395KD Times Cited:16 Cited References
Count:48},
abstract = {Cannabinoid receptor 2 (CB2 receptor)
ligands are potential candidates for the
therapy of chronic pain, inflammatory
disorders, atherosclerosis, and
osteoporosis. We describe the development
of pharmacophore models for CB2 receptor
ligands, as well as a pharmacophore-based
virtual screening workflow, which resulted
in 14 hits for experimental follow-up.
Seven compounds were identified with K-i
values below 25 mu M. The CB2
receptor-selective pyridine
tetrahydrocannabinol analogue 8 (K-i =
1.78 mu M) was identified as a CB2 partial
agonist. Acetamides 12 (K-i = 1.35 mu M)
and 18 (K-i = 2.1 mu M) represent new
scaffolds for CB2 receptor-selective
antagonists and inverse agonists,
respectively. Overall, our
pharmacophore-based workflow yielded three
novel scaffolds for the chemical
development of CB2 receptor ligands.},
keywords = {peripheral cannabinoid receptor selective
agonists docking analysis homology models
derivatives antagonist inhibitors potent
pharmacology protein},
ISSN = {0022-2623},
DOI = {10.1021/Jm801044g},
url = {Go to ISI://WOS:000262522100016
http://pubs.acs.org/doi/pdfplus/10.1021/jm801044g},
year = {2009},
type = {Journal Article}
}
x
Discovery of novel CB2 receptor ligands by a pharmacophore-based virtual screening workflow
Cannabinoid receptor 2 (CB2 receptor) ligands are potential candidates for the therapy of chronic pain, inflammatory disorders, atherosclerosis, and osteoporosis. We describe the development of pharmacophore models for CB2 receptor ligands, as well as a pharmacophore-based virtual screening workflow, which resulted in 14 hits for experimental follow-up. Seven compounds were identified with K-i values below 25 mu M. The CB2 receptor-selective pyridine tetrahydrocannabinol analogue 8 (K-i = 1.78 mu M) was identified as a CB2 partial agonist. Acetamides 12 (K-i = 1.35 mu M) and 18 (K-i = 2.1 mu M) represent new scaffolds for CB2 receptor-selective antagonists and inverse agonists, respectively. Overall, our pharmacophore-based workflow yielded three novel scaffolds for the chemical development of CB2 receptor ligands.
A. Perdih, A. Kovac, G. Wolber, D. Blanot, S. Gobec, and T. Solmajer. Discovery of novel benzene 1,3-dicarboxylic acid inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach, Bioorg Med Chem Lett, 19(10):2668-2673, 2009.
Links:
[doi:10.1016/J.Bmcl.2009.03.141]
[show BibTeX]
[show abstract]
x
@article{RN77,
author = {Perdih, A. and Kovac, A. and Wolber, G.
and Blanot, D. and Gobec, S. and Solmajer,
T.},
title = {Discovery of novel benzene
1,3-dicarboxylic acid inhibitors of
bacterial MurD and MurE ligases by
structure-based virtual screening
approach},
journal = {Bioorganic & Medicinal Chemistry
Letters},
volume = {19},
number = {10},
pages = {2668-2673},
note = {439LE Times Cited:31 Cited References
Count:37},
abstract = {The peptidoglycan biosynthetic pathway
provides an array of potential targets for
antibacterial drug design, attractive
especially with respect to selective
toxicity. Within this pathway, the members
of the Mur ligase family are considered as
promising emerging targets for novel
antibacterial drug design. Based on the
available MurD crystal structures
co-crystallised with N-sulfonyl glutamic
acid inhibitors, a virtual screening
campaign was performed, combining
three-dimensional structure-based
pharmacophores and molecular docking
calculations. A novel class of glutamic
acid surrogates-benzene 1,3-dicarboxylic
acid derivatives-were identified and
compounds 14 and 16 found to possess dual
MurD and MurE inhibitory activity. (C)
2009 Elsevier Ltd. All rights reserved.},
keywords = {murd and mure enzymes virtual screening
three-dimensional structure-based
pharmacophores molecular docking
antibacterial agents drug design
biosynthesis enzymes murd cell-wall
biosynthesis alanyl-d-glutamate
peptidoglycan biosynthesis
escherichia-coli phosphinate inhibitors
l-alanine pharmacophores derivatives
phosphate},
ISSN = {0960-894X},
DOI = {10.1016/J.Bmcl.2009.03.141},
url = {Go to ISI://WOS:000265627800012
http://ac.els-cdn.com/S0960894X09004636/1-s2.0-S0960894X09004636-main.pdf?_tid= 43459adc-4241-11e4-9734-00000aab0f26&acdnat=1411381059_aed1d3bb32f8155b76efdb290240e17c},
year = {2009},
type = {Journal Article}
}
x
Discovery of novel benzene 1,3-dicarboxylic acid inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach
The peptidoglycan biosynthetic pathway provides an array of potential targets for antibacterial drug design, attractive especially with respect to selective toxicity. Within this pathway, the members of the Mur ligase family are considered as promising emerging targets for novel antibacterial drug design. Based on the available MurD crystal structures co-crystallised with N-sulfonyl glutamic acid inhibitors, a virtual screening campaign was performed, combining three-dimensional structure-based pharmacophores and molecular docking calculations. A novel class of glutamic acid surrogates-benzene 1,3-dicarboxylic acid derivatives-were identified and compounds 14 and 16 found to possess dual MurD and MurE inhibitory activity. (C) 2009 Elsevier Ltd. All rights reserved.
J. M. Rollinger, D. Schuster, B. Danzl, S. Schwalger, P. Markt, M. Schmidtke, J. Gertsch, S. Raduner, G. Wolber, T. Langer, and H. Stuppner. In silico target fishing for rationalized ligand discovery exemplified on constituents of Ruta Graveolens, Planta Med, 75(3):195-204, 2009.
Links:
[doi:10.1055/S-0028-1088397]
[show BibTeX]
[show abstract]
x
@article{RN81,
author = {Rollinger, J. M. and Schuster, D. and
Danzl, B. and Schwalger, S. and Markt, P.
and Schmidtke, M. and Gertsch, J. and
Raduner, S. and Wolber, G. and Langer, T.
and Stuppner, H.},
title = {In silico target fishing for rationalized
ligand discovery exemplified on
constituents of Ruta Graveolens},
journal = {Planta Medica},
volume = {75},
number = {3},
pages = {195-204},
note = {417FD Times Cited:35 Cited References
Count:48},
abstract = {The identification of targets whose
interaction is likely to result in the
successful treatment of a disease is of
growing interest for natural product
scientists. In the Current Study we
performed an exemplary application of a
virtual parallel screening approach to
identify potential targets for 16
secondary metabolites isolated and
identified from the aerial parts of the
medicinal plant Ruta graveolens L. Low
energy conformers of the isolated
constituents were simultaneously screened
against a set of 2208 pharmacophore models
generated in-house for the in silico
prediction of putative biological targets,
i.e., target fishing, Based on the
predicted ligand-target interactions, we
focused on three biological targets,
namely acetylcholinesterase (AChE), the
human rhinovirus (HRV) coat protein and
the cannabinoid receptor type-2 (CB(2)).
For a critical evaluation of the applied
parallel screening approach, virtual hits
and non-hits were assayed on the
respective targets. For AChE the highest
scoring virtual hit, arborinine, showed
the best inhibitory in vitro activity on
AChE (IC(50) 34.7 mu M). Determination of
the anti-HRV-2 effect revealed
6,7,8-trimethoxycoumarin and arborinine to
be the most active antiviral constituents
with IC(50) values of 11.98 mu M and 3.19
mu M, respectively. Of these, arborinine
was predicted virtually. Of all the
molecules subjected to parallel screening,
one virtual CB(2) ligand was obtained,
i.e., rutamarin. Interestingly, in
experimental Studies only this compound
showed a selective activity to the CB(2)
receptor (Ki of 7.4 mu M) by using a
radioligand displacement assay. The
applied parallel screening paradigm with
constituents of R. graveolens on three
different proteins has shown promise as an
in silico tool for rational target fishing
and pharmacological profiling of extracts
and single chemical entities in natural
product research.},
keywords = {ruta graveolens l. rutaceae pharmacophore
modelling virtual parallel screening
acetylcholinesterase cannabinoid receptor
2 human rhinovirus coat protein rhinovirus
coat protein natural-products
acetylcholinesterase inhibitors quinoline
alkaloids drug discovery pharmacology
derivatives bioactivity wirkstoffe
coumarin},
ISSN = {0032-0943},
DOI = {10.1055/S-0028-1088397},
url = {Go to ISI://WOS:000264061000001
https://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0028-1088397.pdf},
year = {2009},
type = {Journal Article}
}
x
In silico target fishing for rationalized ligand discovery exemplified on constituents of Ruta Graveolens
The identification of targets whose interaction is likely to result in the successful treatment of a disease is of growing interest for natural product scientists. In the Current Study we performed an exemplary application of a virtual parallel screening approach to identify potential targets for 16 secondary metabolites isolated and identified from the aerial parts of the medicinal plant Ruta graveolens L. Low energy conformers of the isolated constituents were simultaneously screened against a set of 2208 pharmacophore models generated in-house for the in silico prediction of putative biological targets, i.e., target fishing, Based on the predicted ligand-target interactions, we focused on three biological targets, namely acetylcholinesterase (AChE), the human rhinovirus (HRV) coat protein and the cannabinoid receptor type-2 (CB(2)). For a critical evaluation of the applied parallel screening approach, virtual hits and non-hits were assayed on the respective targets. For AChE the highest scoring virtual hit, arborinine, showed the best inhibitory in vitro activity on AChE (IC(50) 34.7 mu M). Determination of the anti-HRV-2 effect revealed 6,7,8-trimethoxycoumarin and arborinine to be the most active antiviral constituents with IC(50) values of 11.98 mu M and 3.19 mu M, respectively. Of these, arborinine was predicted virtually. Of all the molecules subjected to parallel screening, one virtual CB(2) ligand was obtained, i.e., rutamarin. Interestingly, in experimental Studies only this compound showed a selective activity to the CB(2) receptor (Ki of 7.4 mu M) by using a radioligand displacement assay. The applied parallel screening paradigm with constituents of R. graveolens on three different proteins has shown promise as an in silico tool for rational target fishing and pharmacological profiling of extracts and single chemical entities in natural product research.
P. Tiikkainen, P. Markt, G. Wolber, J. Kirchmair, S. Distinto, A. Poso, and O. Kallioniemi. Critical comparison of virtual screening methods against the MUV data set, J Chem Inf Model, 49(10):2168-2178, 2009.
Links:
[doi:10.1021/Ci900249b]
[show BibTeX]
[show abstract]
x
@article{RN76,
author = {Tiikkainen, P. and Markt, P. and Wolber,
G. and Kirchmair, J. and Distinto, S. and
Poso, A. and Kallioniemi, O.},
title = {Critical comparison of virtual screening
methods against the MUV data set},
journal = {Journal of Chemical Information and
Modeling},
volume = {49},
number = {10},
pages = {2168-2178},
note = {509JJ Times Cited:16 Cited References
Count:36},
abstract = {In the current work, we measure the
performance of seven ligand-based virtual
screening tools - five similarity search
methods and two pharmacophore elucidators
- against the MUV data set. For the
similarity search tools, single active
molecules as well as active compound sets
clustered in terms of their chemical
diversity were used as templates., Their
score was calculated against all inactive
and active compounds in their target
class. Subsequently, the scores were used
to calculate different performance metrics
in eluding enrichment factors and AUC
values. We also studied the effect of data
fusion on the results. To measure the
performance of the pharmacophore tools, a
set of active molecules was picked either
random- or chemical diversity-based from
each target class to build a pharmacophore
model which was then used to screen the
remaining compounds in the set. Our
results indicate that template sets
selected by their chemical diversity are
the best choice for similarity search
tools, whereas the optimal training sets
for pharmacophore elucidators are based on
random selection underscoring that
pharmacophore modeling cannot be easily
automated. We also suggest a number of
improvements for future benchmark sets and
discuss activity cliffs as a potential
problem in ligand-based virtual
screening.},
keywords = {body molecular superposition similarity
function data fusion optimization docking
brutus shape},
ISSN = {1549-9596},
DOI = {10.1021/Ci900249b},
url = {Go to ISI://WOS:000271011500003
http://pubs.acs.org/doi/pdfplus/10.1021/ci900249b},
year = {2009},
type = {Journal Article}
}
x
Critical comparison of virtual screening methods against the MUV data set
In the current work, we measure the performance of seven ligand-based virtual screening tools - five similarity search methods and two pharmacophore elucidators - against the MUV data set. For the similarity search tools, single active molecules as well as active compound sets clustered in terms of their chemical diversity were used as templates., Their score was calculated against all inactive and active compounds in their target class. Subsequently, the scores were used to calculate different performance metrics in eluding enrichment factors and AUC values. We also studied the effect of data fusion on the results. To measure the performance of the pharmacophore tools, a set of active molecules was picked either random- or chemical diversity-based from each target class to build a pharmacophore model which was then used to screen the remaining compounds in the set. Our results indicate that template sets selected by their chemical diversity are the best choice for similarity search tools, whereas the optimal training sets for pharmacophore elucidators are based on random selection underscoring that pharmacophore modeling cannot be easily automated. We also suggest a number of improvements for future benchmark sets and discuss activity cliffs as a potential problem in ligand-based virtual screening.
J. Kirchmair, S. Distinto, D. Schuster, G. Spitzer, T. Langer, and G. Wolber. Enhancing drug discovery through in silico screening: Strategies to increase true positives retrieval rates, Curr Med Chem, 15(20):2040-2053, 2008.
Links:
[doi:10.2174/092986708785132843]
[show BibTeX]
[show abstract]
x
@article{RN90,
author = {Kirchmair, J. and Distinto, S. and
Schuster, D. and Spitzer, G. and Langer,
T. and Wolber, G.},
title = {Enhancing drug discovery through in
silico screening: Strategies to increase
true positives retrieval rates},
journal = {Current Medicinal Chemistry},
volume = {15},
number = {20},
pages = {2040-2053},
note = {341ZQ Times Cited:46 Cited References
Count:207},
abstract = {Computational chemistry software for lead
discovery has become well established in
pharmaceutical industry and has found its
way to the desktop computers of medicinal
chemists for different purposes, providing
insight on the mode of action and binding
properties, and creating new ideas for
lead structure refinement. In this review
we investigate the performance and
reliability of recent state-of-the-art
data modeling techniques, as well as
ligand-based and structure-based modeling
approaches for 3D virtual screening. We
discuss and summarize recently published
success stories and lately developed
techniques. Parallel screening is one of
these emerging approaches allowing for
efficient activity in silico profiling of
several compounds against different
targets or anti-targets simultaneously.
This is of special interest to medicinal
chemists, as the approach allows revealing
unknown binding modes ('target-fishing')
as well as integrated ADME profiling or -
more generally - the prediction of
off-target effects.},
keywords = {data modeling virtual screening parallel
screening adme/tox profiling activity
profiling target fishing pharmacophore
modeling protein-ligand docking
molecular-field analysis 3-dimensional
quantitative structure protein-ligand
interactions support vector machines
torsade-de-pointes pharmacophore
identification 3d qsar receptor
antagonists coupled receptors lead
generation},
ISSN = {0929-8673},
DOI = {10.2174/092986708785132843},
url = {Go to ISI://WOS:000258754800004
http://www.eurekaselect.com/67389/article},
year = {2008},
type = {Journal Article}
}
x
Enhancing drug discovery through in silico screening: Strategies to increase true positives retrieval rates
Computational chemistry software for lead discovery has become well established in pharmaceutical industry and has found its way to the desktop computers of medicinal chemists for different purposes, providing insight on the mode of action and binding properties, and creating new ideas for lead structure refinement. In this review we investigate the performance and reliability of recent state-of-the-art data modeling techniques, as well as ligand-based and structure-based modeling approaches for 3D virtual screening. We discuss and summarize recently published success stories and lately developed techniques. Parallel screening is one of these emerging approaches allowing for efficient activity in silico profiling of several compounds against different targets or anti-targets simultaneously. This is of special interest to medicinal chemists, as the approach allows revealing unknown binding modes ('target-fishing') as well as integrated ADME profiling or - more generally - the prediction of off-target effects.
J. Kirchmair, P. Markt, S. Distinto, D. Schuster, G. M. Spitzer, K. R. Liedl, T. Langer, and G. Wolber. The Protein Data Bank (PDB), its related services and software tools as key components for in silico guided drug discovery, J Med Chem, 51(22):7021-7040, 2008.
Links:
[doi:10.1021/Jm8005977]
[show BibTeX]
x
@article{RN83,
author = {Kirchmair, J. and Markt, P. and Distinto,
S. and Schuster, D. and Spitzer, G. M. and
Liedl, K. R. and Langer, T. and Wolber,
G.},
title = {The Protein Data Bank (PDB), its related
services and software tools as key
components for in silico guided drug
discovery},
journal = {Journal of Medicinal Chemistry},
volume = {51},
number = {22},
pages = {7021-7040},
note = {374PQ Times Cited:41 Cited References
Count:199},
keywords = {ligand-binding-sites web-accessible
database structural genomics structure
alignment crystal-structures molecular
docking force-field x-ray functional
annotation automatic-generation},
ISSN = {0022-2623},
DOI = {10.1021/Jm8005977},
url = {Go to ISI://WOS:000261056600001
http://pubs.acs.org/doi/pdfplus/10.1021/jm8005977},
year = {2008},
type = {Journal Article}
}
J. Kirchmair, P. Markt, S. Distinto, G. Wolber, and T. Langer. Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection - What can we learn from earlier mistakes?, J Comput Aided Mol Des, 22(3-4):213-228, 2008.
Links:
[doi:10.1007/S10822-007-9163-6]
[show BibTeX]
[show abstract]
x
@article{RN96,
author = {Kirchmair, J. and Markt, P. and Distinto,
S. and Wolber, G. and Langer, T.},
title = {Evaluation of the performance of 3D
virtual screening protocols: RMSD
comparisons, enrichment assessments, and
decoy selection - What can we learn from
earlier mistakes?},
journal = {Journal of Computer-Aided Molecular
Design},
volume = {22},
number = {3-4},
pages = {213-228},
note = {277XW Times Cited:114 Cited References
Count:85},
abstract = {Within the last few years a considerable
amount of evaluative studies has been
published that investigate the performance
of 3D virtual screening approaches.
Thereby, in particular assessments of
protein-ligand docking are facing
remarkable interest in the scientific
community. However, comparing virtual
screening approaches is a non-trivial
task. Several publications, especially in
the field of molecular docking, suffer
from shortcomings that are likely to
affect the significance of the results
considerably. These quality issues often
arise from poor study design, biasing, by
using improper or inexpressive enrichment
descriptors, and from errors in
interpretation of the data output. In this
review we analyze recent literature
evaluating 3D virtual screening methods,
with focus on molecular docking. We
highlight problematic issues and provide
guidelines on how to improve the quality
of computational studies. Since 3D virtual
screening protocols are in general
assessed by their ability to discriminate
between active and inactive compounds, we
summarize the impact of the composition
and preparation of test sets on the
outcome of evaluations. Moreover, we
investigate the significance of both
classic enrichment parameters and advanced
descriptors for the performance of 3D
virtual screening methods. Furthermore, we
review the significance and suitability of
RMSD as a measure for the accuracy of
protein-ligand docking algorithms and of
conformational space sub sampling
algorithms.},
keywords = {virtual screening evaluation of
computational methods pharmacophore
modeling protein-ligand docking enrichment
descriptors decoy selection virtual
library design tautomerism rmsd
protein-ligand docking high-throughput
docking incremental construction algorithm
automated molecular docking library design
drug design pharmacophore models chemical
similarity genetic algorithm scoring
functions},
ISSN = {0920-654X},
DOI = {10.1007/S10822-007-9163-6},
url = {Go to ISI://WOS:000254249000011
http://download.springer.com/static/pdf/2/art%253A10.1007%252Fs10822-007-9163-6.pdf?auth66= 1411553689_abca80d2ea67a9f6fee936fbdcf3f65a&ext=.pdf},
year = {2008},
type = {Journal Article}
}
x
Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection - What can we learn from earlier mistakes?
Within the last few years a considerable amount of evaluative studies has been published that investigate the performance of 3D virtual screening approaches. Thereby, in particular assessments of protein-ligand docking are facing remarkable interest in the scientific community. However, comparing virtual screening approaches is a non-trivial task. Several publications, especially in the field of molecular docking, suffer from shortcomings that are likely to affect the significance of the results considerably. These quality issues often arise from poor study design, biasing, by using improper or inexpressive enrichment descriptors, and from errors in interpretation of the data output. In this review we analyze recent literature evaluating 3D virtual screening methods, with focus on molecular docking. We highlight problematic issues and provide guidelines on how to improve the quality of computational studies. Since 3D virtual screening protocols are in general assessed by their ability to discriminate between active and inactive compounds, we summarize the impact of the composition and preparation of test sets on the outcome of evaluations. Moreover, we investigate the significance of both classic enrichment parameters and advanced descriptors for the performance of 3D virtual screening methods. Furthermore, we review the significance and suitability of RMSD as a measure for the accuracy of protein-ligand docking algorithms and of conformational space sub sampling algorithms.
P. Markt, C. McGoohan, B. Walker, J. Kirchmair, C. L. Feldmann, G. De Martino, G. Spitzer, S. Distinto, D. Schuster, G. Wolber, C. Laggner, and T. Langer. Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening, J Chem Inf Model, 48(8):1693-1705, 2008.
Links:
[doi:10.1021/Ci800101j]
[show BibTeX]
[show abstract]
x
@article{RN91,
author = {Markt, P. and McGoohan, C. and Walker, B.
and Kirchmair, J. and Feldmann, C. L. and
De Martino, G. and Spitzer, G. and
Distinto, S. and Schuster, D. and Wolber,
G. and Laggner, C. and Langer, T.},
title = {Discovery of novel cathepsin S inhibitors
by pharmacophore-based virtual
high-throughput screening},
journal = {Journal of Chemical Information and
Modeling},
volume = {48},
number = {8},
pages = {1693-1705},
note = {341EQ Times Cited:9 Cited References
Count:42},
abstract = {The cysteine protease cathepsin S (CatS)
is involved in the pathogenesis of
autoimmune disorders, atherosclerosis, and
obesity. Therefore, it represents a
promising pharmacological target for drug
development. We generated ligand-based and
structure-based pharmacophore models for
noncovalent and covalent CatS inhibitors
to perform virtual high-throughput
screening of chemical databases in order
to discover novel scaffolds for CatS
inhibitors. An in vitro evaluation of the
resulting 15 structures revealed seven
CatS inhibitors with kinetic constants in
the low micromolar range. These compounds
can be subjected to further chemical
modifications to obtain drugs for the
treatment of autoimmune disorders and
atherosclerosis.},
keywords = {k inhibitors noncovalent inhibitors
arylaminoethyl amides cysteine proteases
design potent docking binding models
series},
ISSN = {1549-9596},
DOI = {10.1021/Ci800101j},
url = {Go to ISI://WOS:000258697400015
http://pubs.acs.org/doi/pdfplus/10.1021/ci800101j},
year = {2008},
type = {Journal Article}
}
x
Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening
The cysteine protease cathepsin S (CatS) is involved in the pathogenesis of autoimmune disorders, atherosclerosis, and obesity. Therefore, it represents a promising pharmacological target for drug development. We generated ligand-based and structure-based pharmacophore models for noncovalent and covalent CatS inhibitors to perform virtual high-throughput screening of chemical databases in order to discover novel scaffolds for CatS inhibitors. An in vitro evaluation of the resulting 15 structures revealed seven CatS inhibitors with kinetic constants in the low micromolar range. These compounds can be subjected to further chemical modifications to obtain drugs for the treatment of autoimmune disorders and atherosclerosis.
P. Markt, R. K. Petersen, E. N. Flindt, K. Krjstiansen, J. Kirchmair, G. Spitzer, S. Distinto, D. Schuster, G. Wolber, C. Laggner, and T. Langer. Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening, J Med Chem, 51(20):6303-6317, 2008.
Links:
[doi:10.1021/Jm800128k]
[show BibTeX]
[show abstract]
x
@article{RN85,
author = {Markt, P. and Petersen, R. K. and Flindt,
E. N. and Krjstiansen, K. and Kirchmair,
J. and Spitzer, G. and Distinto, S. and
Schuster, D. and Wolber, G. and Laggner,
C. and Langer, T.},
title = {Discovery of novel PPAR ligands by a
virtual screening approach based on
pharmacophore modeling, 3D shape, and
electrostatic similarity screening},
journal = {Journal of Medicinal Chemistry},
volume = {51},
number = {20},
pages = {6303-6317},
note = {361BO Times Cited:28 Cited References
Count:51},
abstract = {Peroxisome proliferator-activated
receptors (PPARs) are important targets
for drugs used in the treatment of
atherosclerosis, dyslipidaemia, obesity,
type 2 diabetes, and other diseases caused
by abnormal regulation of the glucose and
lipid metabolism. We applied a virtual
screening workflow based on a combination
of pharmacophore modeling with 3D shape
and electrostatic similarity screening
techniques to discover novel scaffolds for
PPAR ligands. From the resulting 10
virtual screening hits, five tested
positive in human PPAR ligand-binding
domain (hPPAR-LBD) transactivation assays
and showed affinities for PPAR in a
competitive binding assay. Compounds 5, 7,
and 8 were identified as PPAR-alpha
agonists, whereas compounds 2 and 9 showed
agonistic activity for hPPAR-gamma.
Moreover, compound 9 was identified as a
PPAR-delta antagonist. These results
demonstrate that our virtual screening
protocol is able to enrich novel scaffolds
for PPAR ligands that could be useful for
drug development in the area of
atherosclerosis, dyslipidaemia, and type 2
diabetes.},
keywords = {proliferator-activated-receptor
fatty-acids in-vitro delta gamma
antagonist alpha agonist drugs},
ISSN = {0022-2623},
DOI = {10.1021/Jm800128k},
url = {Go to ISI://WOS:000260102700008
http://pubs.acs.org/doi/pdfplus/10.1021/jm800128k},
year = {2008},
type = {Journal Article}
}
x
Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening
Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.
D. Schuster, L. G. Nashev, J. Kirchmair, C. Laggner, G. Wolber, T. Langer, and A. Odermatt. Discovery of nonsteroidal 17β-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries, J Med Chem, 51(14):4188-4199, 2008.
Links:
[doi:10.1021/Jm800054h]
[show BibTeX]
[show abstract]
x
@article{RN92,
author = {Schuster, D. and Nashev, L. G. and
Kirchmair, J. and Laggner, C. and Wolber,
G. and Langer, T. and Odermatt, A.},
title = {Discovery of nonsteroidal
17β-hydroxysteroid dehydrogenase 1
inhibitors by pharmacophore-based
screening of virtual compound libraries},
journal = {Journal of Medicinal Chemistry},
volume = {51},
number = {14},
pages = {4188-4199},
note = {327IA Times Cited:26 Cited References
Count:70},
abstract = {17 beta-Hydroxysteroid dehydrogenase type
1 (17 beta-HSD1) plays a pivotal role in
the local synthesis of the most potent
estrogen estradiol. Its expression is a
prognostic marker for the outcome of
patients with breast cancer and inhibition
of 17 beta-HSD I is currently under
consideration for breast cancer prevention
and treatment. We aimed to identify
nonsteroidal 17 beta-HSD1 inhibitor
scaffolds by virtual screening with
pharmacophore models built from crystal
structures containing steroidal compounds.
The most promising model was validated by
comparing predicted and experimentally
determined inhibitory activities of
several flavonoids. Subsequently, a
virtual library of nonsteroidal compounds
was screened against the 3D pharmacophore.
Analysis of 14 selected compounds yielded
four that inhibited the activity of human
17 beta-HSD1 (IC(50) below 50 mu M).
Specificity assessment of identified 17
beta-HSD1 inhibitors emphasized the
importance of including related
short-chain dehydrogenase/reductase (SDR)
members to analyze off-target effects.
Compound 29 displayed at least 10-fold
selectivity over the related SDR enzymes
tested.},
keywords = {11-beta-hydroxysteroid dehydrogenase
type-1 17-beta-hydroxy steroid
dehydrogenase 3d qsar model breast-cancer
potent inhibitors active-site
prognostic-significance estradiol protein
design},
ISSN = {0022-2623},
DOI = {10.1021/Jm800054h},
url = {Go to ISI://WOS:000257721600013
http://pubs.acs.org/doi/pdfplus/10.1021/jm800054h},
year = {2008},
type = {Journal Article}
}
x
Discovery of nonsteroidal 17β-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries
17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) plays a pivotal role in the local synthesis of the most potent estrogen estradiol. Its expression is a prognostic marker for the outcome of patients with breast cancer and inhibition of 17 beta-HSD I is currently under consideration for breast cancer prevention and treatment. We aimed to identify nonsteroidal 17 beta-HSD1 inhibitor scaffolds by virtual screening with pharmacophore models built from crystal structures containing steroidal compounds. The most promising model was validated by comparing predicted and experimentally determined inhibitory activities of several flavonoids. Subsequently, a virtual library of nonsteroidal compounds was screened against the 3D pharmacophore. Analysis of 14 selected compounds yielded four that inhibited the activity of human 17 beta-HSD1 (IC(50) below 50 mu M). Specificity assessment of identified 17 beta-HSD1 inhibitors emphasized the importance of including related short-chain dehydrogenase/reductase (SDR) members to analyze off-target effects. Compound 29 displayed at least 10-fold selectivity over the related SDR enzymes tested.
G. Wolber, T. Seidel, F. Bendix, and T. Langer. Molecule-pharmacophore superpositioning and pattern matching in computational drug design, Drug Discov Today, 13(1â2):23-29, 2008.
Links:
[doi:10.1016/j.drudis.2007.09.007]
[show BibTeX]
[show abstract]
x
@article{RN190,
author = {Wolber, Gerhard and Seidel, Thomas and
Bendix, Fabian and Langer, Thierry},
title = {Molecule-pharmacophore superpositioning
and pattern matching in computational drug
design},
journal = {Drug Discovery Today},
volume = {13},
number = {1–2},
pages = {23-29},
abstract = {Three-dimensional (3D) pharmacophore
modeling is a technique for describing the
interaction of a small molecule ligand
with a macromolecular target. Since
chemical features in a pharmacophore model
are well known and highly transparent for
medicinal chemists, these models are
intuitively understandable and have been
increasingly successful in computational
drug discovery in the past few years. The
performance and applicability of
pharmacophore modeling depends on two main
factors: the definition and placement of
pharmacophoric features and the alignment
techniques used to overlay 3D
pharmacophore models and small molecules.
An overview of key technologies and latest
developments in the area of 3D
pharmacophores is given and provides
insight into different approaches as
implemented by the 3D pharmacophore
modeling packages like Catalyst, MOE,
Phase and LigandScout.},
ISSN = {1359-6446},
DOI = {10.1016/j.drudis.2007.09.007},
url = {http://www.sciencedirect.com/science/article/pii/S1359644607003996
https://pdf.sciencedirectassets.com/271275/1-s2.0-S1359644607X00230/1-s2.0-S1359644607003996/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJr%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBmGoQIBcjjZ5EaOK3PJ%2FGurZx%2F3iAg7AxgzJBGlS1pLAiEAqq3PoXrNmhK0J8VvhGKQxD8CDm2MMxpACdgEvvCDCF0q2gMIQhACGgwwNTkwMDM1NDY4NjUiDB%2FjPXYQeqnKPMIAZSq3Axc0m%2BRD9Wt3prnTKye3Cqvo0AREbqzZ946GaterseGXxpe%2BUb3tyOJVBoXAsvayOEvYdT75FjY53skFYyeai6OYOXjZRWTEelsGyFCQf8cT3DEzx4Q%2FSuFEL5blDoqhss6bszDRC5%2FuVVpSzUmF7%2BFyAgGxxPdatNCbBmiutHGyRMn4PicJgX1DP70wJovm2MIIfOQjtVBAoW1FPcQfo4A0fJI5ShSReUYAnaXr04R8cTE%2BTTnwOVhgNPw19doX3%2FZOAC3wHvx2xdw427PkU7STXll%2FivSFUP2UPMpj5wiro1CxQicswmv0RAWfVQV%2BoN9oIuCE4eWm%2FoT86KudK0SbLCkH8hiO85Gkxien8zQf3J%2BA2aXelkRNwjG55dMxfLKxuLd5mhDnokYj7cOpwsS9sVe2WOpNw0L83GU%2FpuvVJI9vZFARLk225K%2FQ4b1pFcwGOKOAZBiAQZJ9D7JWTWR0gA8Y9KTN%2FrSCDcM7e3OCrDWcifFbCTor1FSCUFanT4fycawD7p8nphvKBxLQcZTmUo0CLG0aAL6hXvuI45m7qu0ijPUXIyCJTvyurXi9RPRuVGihaxkw98KO6wU6tAGChddaHRM2ELzStD4I3%2BltvO8qU5OvXkFpFPXsJT4YQCQafydsDiutI4rsZ8MyFKk2VmqAYvFy3yg9tm4P88k25cm8YxrYD9FZBt34b46IAXloCTW%2BjWdZAQpgxFCuBBURFwPqw%2Bz5EL4gHYjp%2BQW%2FHnmtR8SfofKETRV74Znvs9OncFyjtB09l8I8dyXKRPvZSo%2BtyGyKRjRStMbqfOcty%2BjSd%2FWSyeoJFlE6ZwZclpM4vEI%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090956Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYQ4T4FY7Z%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=2a92644509fcff0f30c4cecf224e5530afbd057c812b0037e6079eb945c5feaf&hash=942a02e541d3d7bdc91d26f8819910070b90cbdc3b8ab3e2f810af3a5c4c490e&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S1359644607003996&tid=spdf-e78f20c4-403e-4aa3-86d9-9fe590eabea4&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client},
year = {2008},
type = {Journal Article}
}
x
Molecule-pharmacophore superpositioning and pattern matching in computational drug design
Three-dimensional (3D) pharmacophore modeling is a technique for describing the interaction of a small molecule ligand with a macromolecular target. Since chemical features in a pharmacophore model are well known and highly transparent for medicinal chemists, these models are intuitively understandable and have been increasingly successful in computational drug discovery in the past few years. The performance and applicability of pharmacophore modeling depends on two main factors: the definition and placement of pharmacophoric features and the alignment techniques used to overlay 3D pharmacophore models and small molecules. An overview of key technologies and latest developments in the area of 3D pharmacophores is given and provides insight into different approaches as implemented by the 3D pharmacophore modeling packages like Catalyst, MOE, Phase and LigandScout.
J. Kirchmair, S. Ristic, K. Eder, P. Markt, G. Wolber, C. Laggner, and T. Langer. Fast and efficient in silico 3D screening: Toward maximum computational efficiency of pharmacophore-based and shape-based approaches, J Chem Inf Model, 47(6):2182-2196, 2007.
Links:
[doi:10.1021/Ci700024q]
[show BibTeX]
[show abstract]
x
@article{RN100,
author = {Kirchmair, J. and Ristic, S. and Eder, K.
and Markt, P. and Wolber, G. and Laggner,
C. and Langer, T.},
title = {Fast and efficient in silico 3D
screening: Toward maximum computational
efficiency of pharmacophore-based and
shape-based approaches},
journal = {Journal of Chemical Information and
Modeling},
volume = {47},
number = {6},
pages = {2182-2196},
note = {235EO Times Cited:44 Cited References
Count:36},
abstract = {In continuation of our recent studies on
the quality of conformational models
generated with CATALYST and OMEGA we
present a large-scale survey focusing on
the impact of conformational model quality
and several screening parameters on
pharmacophore-based and shape-based
virtual high throughput screening (vHTS).
Therefore, we collected known active
compounds of CDK2, p38 MAPK, PPAR-gamma,
and factor Xa and built a set of druglike
decoys using ilib:diverse. Subsequently,
we generated 3D structures using CORINA
and also calculated conformational models
for all compounds using CAESAR, CATALYST
FAST, and OMEGA. A widespread set of 103
structure-based pharmacophore models was
developed with LigandScout for virtual
screening with CATALYST. The performance
of both database search modes (FAST and
BEST flexible database search) as well as
the fit value calculation procedures (FAST
and BEST fit) available in CATALYST were
analyzed in terms of their ability to
discriminate between active and inactive
compounds and in terms of efficiency.
Moreover, these results are put in direct
comparison to the performance of the
shape-based virtual screening platform
ROCS. Our results prove that high
enrichment rates are not necessarily in
conflict with efficient vHTS settings: In
most of the experiments, we obtained the
highest yield of actives in the hit list
when parameter sets for the fastest search
algorithm were used.},
keywords = {protein-bound ligands conformational
space inhibitors catalyst receptor binding
design kinases models},
ISSN = {1549-9596},
DOI = {10.1021/Ci700024q},
url = {Go to ISI://WOS:000251216500016
http://pubs.acs.org/doi/pdfplus/10.1021/ci700024q},
year = {2007},
type = {Journal Article}
}
x
Fast and efficient in silico 3D screening: Toward maximum computational efficiency of pharmacophore-based and shape-based approaches
In continuation of our recent studies on the quality of conformational models generated with CATALYST and OMEGA we present a large-scale survey focusing on the impact of conformational model quality and several screening parameters on pharmacophore-based and shape-based virtual high throughput screening (vHTS). Therefore, we collected known active compounds of CDK2, p38 MAPK, PPAR-gamma, and factor Xa and built a set of druglike decoys using ilib:diverse. Subsequently, we generated 3D structures using CORINA and also calculated conformational models for all compounds using CAESAR, CATALYST FAST, and OMEGA. A widespread set of 103 structure-based pharmacophore models was developed with LigandScout for virtual screening with CATALYST. The performance of both database search modes (FAST and BEST flexible database search) as well as the fit value calculation procedures (FAST and BEST fit) available in CATALYST were analyzed in terms of their ability to discriminate between active and inactive compounds and in terms of efficiency. Moreover, these results are put in direct comparison to the performance of the shape-based virtual screening platform ROCS. Our results prove that high enrichment rates are not necessarily in conflict with efficient vHTS settings: In most of the experiments, we obtained the highest yield of actives in the hit list when parameter sets for the fastest search algorithm were used.
J. Kirchmair, G. Wolber, C. Laggner, and T. Langer. Comparative performance assessment of the conformational model generators omega and catalyst: A large-scale survey on the retrieval of protein-bound ligand conformations, J Chem Inf Model, 46(4):1848-1861, 2006.
Links:
[doi:10.1021/Ci060084g]
[show BibTeX]
[show abstract]
x
@article{RN111,
author = {Kirchmair, J. and Wolber, G. and Laggner,
C. and Langer, T.},
title = {Comparative performance assessment of the
conformational model generators omega and
catalyst: A large-scale survey on the
retrieval of protein-bound ligand
conformations},
journal = {Journal of Chemical Information and
Modeling},
volume = {46},
number = {4},
pages = {1848-1861},
note = {066BM Times Cited:91 Cited References
Count:22},
abstract = {In continuation of our studies to
evaluate the ability of various conformer
generators to produce bioactive
conformations, we present the extension of
our work on the analysis of Catalyst's
conformational subsampling algorithm in a
comparative evaluation with OpenEye's
currently updated tool Omega 2.0. Our
study is based on an enhanced test set of
778 drug molecules and pharmacologically
relevant compounds extracted from the
Protein Data Bank (PDB). We elaborated
protocols for two common conformer
generation use cases and applied them to
both programs: (i) high-throughput
settings for processing large databases
and (ii) high-quality settings for binding
site exploration or lead structure
refinement. While Catalyst is faster in
the first case, Omega 2.0 better
reproduces the bound ligand conformations
from the PDB in less time for the latter
case.},
keywords = {energy minimization coverage respect
binding},
ISSN = {1549-9596},
DOI = {10.1021/Ci060084g},
url = {Go to ISI://WOS:000239204400032
http://pubs.acs.org/doi/pdfplus/10.1021/ci060084g},
year = {2006},
type = {Journal Article}
}
x
Comparative performance assessment of the conformational model generators omega and catalyst: A large-scale survey on the retrieval of protein-bound ligand conformations
In continuation of our studies to evaluate the ability of various conformer generators to produce bioactive conformations, we present the extension of our work on the analysis of Catalyst's conformational subsampling algorithm in a comparative evaluation with OpenEye's currently updated tool Omega 2.0. Our study is based on an enhanced test set of 778 drug molecules and pharmacologically relevant compounds extracted from the Protein Data Bank (PDB). We elaborated protocols for two common conformer generation use cases and applied them to both programs: (i) high-throughput settings for processing large databases and (ii) high-quality settings for binding site exploration or lead structure refinement. While Catalyst is faster in the first case, Omega 2.0 better reproduces the bound ligand conformations from the PDB in less time for the latter case.
T. M. Steindl, D. Schuster, G. Wolber, C. Laggner, and T. Langer. High-throughput structure-based pharmacophore modelling as a basis for successful parallel virtual screening, J Comput Aided Mol Des, 20(12):703-715, 2006.
Links:
[doi:10.1007/S10822-006-9066-Y]
[show BibTeX]
[show abstract]
x
@article{RN107,
author = {Steindl, T. M. and Schuster, D. and
Wolber, G. and Laggner, C. and Langer,
T.},
title = {High-throughput structure-based
pharmacophore modelling as a basis for
successful parallel virtual screening},
journal = {Journal of Computer-Aided Molecular
Design},
volume = {20},
number = {12},
pages = {703-715},
note = {134OY Times Cited:26 Cited References
Count:23},
abstract = {In order to assess bioactivity profiles
for small organic molecules we propose to
use parallel pharmacophore-based virtual
screening. Our aim is to provide a fast,
reliable and scalable system that allows
for rapid in silico activity profile
prediction of virtual molecules. In this
proof of principle study, carried out with
the new structure-based pharmacophore
modelling tool LigandScout and the
high-performance database mining platform
Catalyst, we present a model work for the
application of parallel
pharmacophore-based virtual screening on a
set of 50 structure-based pharmacophore
models built for various viral targets and
100 antiviral compounds. The latter were
screened against all pharmacophore models
in order to determine if their known
biological targets could be correctly
predicted via an enrichment of
corresponding pharmacophores matching
these ligands. The results demonstrate
that the desired enrichment, i.e. a
successful activity profiling, was
achieved for approximately 90% of all
input molecules. Additionally, we discuss
descriptors for output validation, as well
as various aspects influencing the
analysis of the obtained activity
profiles, and the effect of the searching
mode utilized for screening. The results
of the study presented here clearly
indicate that pharmacophore-based parallel
screening comprises a reliable in silico
method to predict the potential biological
activities of a compound or a compound
library by screening it against a series
of pharmacophore queries.},
keywords = {bioactivity profiling virtual screening
pharmacophore modelling ligandscout
structure-based pharmacophores database
mining parallel screening bound ligand
conformations inhibitors identification
discovery design drugs},
ISSN = {0920-654X},
DOI = {10.1007/S10822-006-9066-Y},
url = {Go to ISI://WOS:000244093900001
http://download.springer.com/static/pdf/684/art%253A10.1007%252Fs10822-006-9066-y.pdf?auth66= 1411553713_72bc8c2cb9696a511117bc424b9e7d17&ext=.pdf},
year = {2006},
type = {Journal Article}
}
x
High-throughput structure-based pharmacophore modelling as a basis for successful parallel virtual screening
In order to assess bioactivity profiles for small organic molecules we propose to use parallel pharmacophore-based virtual screening. Our aim is to provide a fast, reliable and scalable system that allows for rapid in silico activity profile prediction of virtual molecules. In this proof of principle study, carried out with the new structure-based pharmacophore modelling tool LigandScout and the high-performance database mining platform Catalyst, we present a model work for the application of parallel pharmacophore-based virtual screening on a set of 50 structure-based pharmacophore models built for various viral targets and 100 antiviral compounds. The latter were screened against all pharmacophore models in order to determine if their known biological targets could be correctly predicted via an enrichment of corresponding pharmacophores matching these ligands. The results demonstrate that the desired enrichment, i.e. a successful activity profiling, was achieved for approximately 90% of all input molecules. Additionally, we discuss descriptors for output validation, as well as various aspects influencing the analysis of the obtained activity profiles, and the effect of the searching mode utilized for screening. The results of the study presented here clearly indicate that pharmacophore-based parallel screening comprises a reliable in silico method to predict the potential biological activities of a compound or a compound library by screening it against a series of pharmacophore queries.
G. Wolber, A. A. Dornhofer, and T. Langer. Efficient overlay of small organic molecules using 3D pharmacophores, J Comput Aided Mol Des, 20(12):773-788, 2006.
Links:
[doi:10.1007/S10822-006-9078-7]
[show BibTeX]
[show abstract]
x
@article{RN108,
author = {Wolber, G. and Dornhofer, A. A. and
Langer, T.},
title = {Efficient overlay of small organic
molecules using 3D pharmacophores},
journal = {Journal of Computer-Aided Molecular
Design},
volume = {20},
number = {12},
pages = {773-788},
note = {134OY Times Cited:88 Cited References
Count:26},
abstract = {Aligning and overlaying two or more
bio-active molecules is one of the key
tasks in computational drug discovery and
bio-activity prediction. Especially
chemical-functional molecule
characteristics from the view point of a
macromolecular target represented as a 3D
pharmacophore are the most interesting
similarity measure when describing and
analyzing macromolecule-ligand
interaction. In this study, a novel
approach for aligning rigid
three-dimensional molecules according to
their chemical-functional pharmacophoric
features is presented and compared to the
overlay of experimentally determined poses
in a comparable macromolecule coordinate
frame. The presented approach identifies
optimal chemical feature pairs using
distance and density characteristics
obtained by correlating pharmacophoric
geometries and thus proves to be faster
than existing combinatorial alignment
methods and creates more reasonable
alignments than pure atom-based methods.
Examples will be provided to demonstrate
the feasibility, speed and intuitiveness
of this method.},
keywords = {molecular alignment molecular
superimposition pharmacophore ligandscout
relate 2 sets rotation vectors},
ISSN = {0920-654X},
DOI = {10.1007/S10822-006-9078-7},
url = {Go to ISI://WOS:000244093900006
http://download.springer.com/static/pdf/37/art%253A10.1007%252Fs10822-006-9078-7.pdf?auth66= 1411553718_b433790d8568698a69115ed9e9065dde&ext=.pdf},
year = {2006},
type = {Journal Article}
}
x
Efficient overlay of small organic molecules using 3D pharmacophores
Aligning and overlaying two or more bio-active molecules is one of the key tasks in computational drug discovery and bio-activity prediction. Especially chemical-functional molecule characteristics from the view point of a macromolecular target represented as a 3D pharmacophore are the most interesting similarity measure when describing and analyzing macromolecule-ligand interaction. In this study, a novel approach for aligning rigid three-dimensional molecules according to their chemical-functional pharmacophoric features is presented and compared to the overlay of experimentally determined poses in a comparable macromolecule coordinate frame. The presented approach identifies optimal chemical feature pairs using distance and density characteristics obtained by correlating pharmacophoric geometries and thus proves to be faster than existing combinatorial alignment methods and creates more reasonable alignments than pure atom-based methods. Examples will be provided to demonstrate the feasibility, speed and intuitiveness of this method.
J. Kirchmair, C. Laggner, G. Wolber, and T. Langer. Comparative analysis of protein-bound ligand conformations with respect to catalyst's conformational space subsampling algorithms, J Chem Inf Model, 45(2):422-430, 2005.
Links:
[doi:10.1021/Ci0497531]
[show BibTeX]
[show abstract]
x
@article{RN116,
author = {Kirchmair, J. and Laggner, C. and Wolber,
G. and Langer, T.},
title = {Comparative analysis of protein-bound
ligand conformations with respect to
catalyst's conformational space
subsampling algorithms},
journal = {Journal of Chemical Information and
Modeling},
volume = {45},
number = {2},
pages = {422-430},
note = {911PZ Times Cited:68 Cited References
Count:26},
abstract = {We examined the quality of Catalyst's
conformational model generation algorithm
via a large scale study based on the
crystal structures of a sample of 510
pharmaceutically relevant protein-ligand
complexes extracted from the Protein Data
Bank (PDB). Our results show that the
tested algorithms implemented within
Catalyst are able to produce high quality
conformers, which in most of the cases are
well suited for in silico drug research.
Catalyst-specific settings were analyzed,
such as the method used for the
conformational model generation (FAST vs
BEST) and the maximum number of generated
conformers. By setting these options for
higher fitting quality, the average RMS
values describing the similarity of
experimental and simulated conformers were
improved from an RMS of 1.06 with max. 50
FAST generated conformers to an RMS of
0.93 with max. 255 BEST generated
conformers, which represents an
improvement by 12%. Each method provides
best fitting conformers with an RMS value
1.50 in more than 80% of all cases. We
analyzed the computing time/quality ratio
of various conformational model generation
settings and examined ligands in high
energy conformations. Furthermore,
properties of the same ligands in various
proteins were investigated, and the
fitting qualities of experimental
conformations from the PDB and the
Cambridge Structural Database (CSD) were
compared. One of the most important
conclusions of former studies, the fact
that bioactive conformers often have
energy high above that of Global minima,
was confirmed.},
keywords = {enzyme action active-site coverage
binding},
ISSN = {1549-9596},
DOI = {10.1021/Ci0497531},
url = {Go to ISI://WOS:000228018000028
http://pubs.acs.org/doi/pdfplus/10.1021/ci049753l},
year = {2005},
type = {Journal Article}
}
x
Comparative analysis of protein-bound ligand conformations with respect to catalyst's conformational space subsampling algorithms
We examined the quality of Catalyst's conformational model generation algorithm via a large scale study based on the crystal structures of a sample of 510 pharmaceutically relevant protein-ligand complexes extracted from the Protein Data Bank (PDB). Our results show that the tested algorithms implemented within Catalyst are able to produce high quality conformers, which in most of the cases are well suited for in silico drug research. Catalyst-specific settings were analyzed, such as the method used for the conformational model generation (FAST vs BEST) and the maximum number of generated conformers. By setting these options for higher fitting quality, the average RMS values describing the similarity of experimental and simulated conformers were improved from an RMS of 1.06 with max. 50 FAST generated conformers to an RMS of 0.93 with max. 255 BEST generated conformers, which represents an improvement by 12%. Each method provides best fitting conformers with an RMS value < 1.50 in more than 80% of all cases. We analyzed the computing time/quality ratio of various conformational model generation settings and examined ligands in high energy conformations. Furthermore, properties of the same ligands in various proteins were investigated, and the fitting qualities of experimental conformations from the PDB and the Cambridge Structural Database (CSD) were compared. One of the most important conclusions of former studies, the fact that bioactive conformers often have energy high above that of Global minima, was confirmed.
G. Wolber, and T. Langer. LigandScout: 3D pharmacophores derived from protein-bound Ligands and their use as virtual screening filters, J Chem Inf Model, 45(1):160-169, 2005.
Links:
[doi:10.1021/Ci049885e]
[show BibTeX]
[show abstract]
x
@article{RN117,
author = {Wolber, G. and Langer, T.},
title = {LigandScout: 3D pharmacophores derived
from protein-bound Ligands and their use
as virtual screening filters},
journal = {Journal of Chemical Information and
Modeling},
volume = {45},
number = {1},
pages = {160-169},
note = {911DU Times Cited:351 Cited References
Count:42},
abstract = {From the historically grown archive of
protein-ligand complexes in the Protein
Data Bank small organic ligands are
extracted and interpreted in terms of
their chemical characteristics and
features. Subsequently, pharmacophores
representing ligand-receptor interaction
are derived from each of these small
molecules and its surrounding amino acids.
Based on a defined set of only six types
of chemical features and volume
constraints, three-dimensional
pharmacophore models are constructed,
which are sufficiently selective to
identify the described binding mode and
are thus a useful tool for in-silico
screening of large compound databases. The
algorithms for ligand extraction and
interpretation as well as the
pharmacophore creation technique from the
automatically interpreted data are
presented and applied to a rhinovirus
capsid complex as application example.},
keywords = {software},
ISSN = {1549-9596},
DOI = {10.1021/Ci049885e},
url = {Go to ISI://WOS:000227982800019
http://pubs.acs.org/doi/pdfplus/10.1021/ci049885e},
year = {2005},
type = {Journal Article}
}
x
LigandScout: 3D pharmacophores derived from protein-bound Ligands and their use as virtual screening filters
From the historically grown archive of protein-ligand complexes in the Protein Data Bank small organic ligands are extracted and interpreted in terms of their chemical characteristics and features. Subsequently, pharmacophores representing ligand-receptor interaction are derived from each of these small molecules and its surrounding amino acids. Based on a defined set of only six types of chemical features and volume constraints, three-dimensional pharmacophore models are constructed, which are sufficiently selective to identify the described binding mode and are thus a useful tool for in-silico screening of large compound databases. The algorithms for ligand extraction and interpretation as well as the pharmacophore creation technique from the automatically interpreted data are presented and applied to a rhinovirus capsid complex as application example.
T. Langer, and G. Wolber. Pharmacophore definition and 3D searches, Drug Discovery Today: Technologies, 1(3):203-207, 2004.
Links:
[doi:10.1016/j.ddtec.2004.11.015]
[show BibTeX]
[show abstract]
x
@article{RN150,
author = {Langer, T. and Wolber, G.},
title = {Pharmacophore definition and 3D
searches},
journal = {Drug Discovery Today: Technologies},
volume = {1},
number = {3},
pages = {203-207},
abstract = {The most common pharmacophore building
concepts based on either 3D structure of
the target or ligand information are
discussed together with the application of
such models as queries for 3D database
search. An overview of the key techniques
available on the market is given and
differences with respect to algorithms
used and performance obtained are
highlighted. Pharmacophore modelling and
3D database search are shown to be
successful tools for enriching screening
experiments aimed at the discovery of
novel bio-active compounds. Section
Editor: Hugo Kubiniyi – University of
Heidelberg, Germany Pharmacophore models
are hypotheses on the 3D arrangement of
structural properties, such as hydrogen
bond donar and acceptor properties,
hydrophobic groups and aromatic rings of
compounds that bind to a biological
target. In the presence of the 3D
structure of this target of by comparison
with inactive analogs, further geometric
and/or steric constraints can be defined.
The article describes and evaluates
strategies and commercial software for
pharmacophore definition, starting from
the 3D structures of ligand-protein
complexes or from ligands alone. Once a
pharmacophore model is established, 3D
searches in large databases can be
performed, leading to a significant
enrichment of active analogs.},
ISSN = {1740-6749},
DOI = {10.1016/j.ddtec.2004.11.015},
url = {http://www.sciencedirect.com/science/article/pii/S1740674904000630
http://ac.els-cdn.com/S1740674904000630/1-s2.0-S1740674904000630-main.pdf?_tid= a8039fb2-4338-11e4-978e-00000aab0f02&acdnat=1411487314_713ac491b1ee97828269b62f0b50e6b6},
year = {2004},
type = {Journal Article}
}
x
Pharmacophore definition and 3D searches
The most common pharmacophore building concepts based on either 3D structure of the target or ligand information are discussed together with the application of such models as queries for 3D database search. An overview of the key techniques available on the market is given and differences with respect to algorithms used and performance obtained are highlighted. Pharmacophore modelling and 3D database search are shown to be successful tools for enriching screening experiments aimed at the discovery of novel bio-active compounds. Section Editor: Hugo Kubiniyi – University of Heidelberg, Germany Pharmacophore models are hypotheses on the 3D arrangement of structural properties, such as hydrogen bond donar and acceptor properties, hydrophobic groups and aromatic rings of compounds that bind to a biological target. In the presence of the 3D structure of this target of by comparison with inactive analogs, further geometric and/or steric constraints can be defined. The article describes and evaluates strategies and commercial software for pharmacophore definition, starting from the 3D structures of ligand-protein complexes or from ligands alone. Once a pharmacophore model is established, 3D searches in large databases can be performed, leading to a significant enrichment of active analogs.
T. Langer, and G. Wolber. Virtual combinatorial chemistry and in silico screening: Efficient tools for lead structure discovery?, Pure Appl Chem, 76(5):991-996, 2004.
Links:
[doi:10.1351/Pac200476050991]
[show BibTeX]
[show abstract]
x
@article{RN118,
author = {Langer, T. and Wolber, G.},
title = {Virtual combinatorial chemistry and in
silico screening: Efficient tools for lead
structure discovery?},
journal = {Pure and Applied Chemistry},
volume = {76},
number = {5},
pages = {991-996},
note = {838DN Times Cited:23 Cited References
Count:14},
abstract = {In this article, an overview of the most
common ligand-based in silico screening
techniques is given together with an
example on the recent successful
application of combined use of
pharmacophore modeling, database mining,
and biological assays. Additionally, a new
approach for structure-based
high-throughput pharmacophore model
generation is presented. The LigandScout
program contains an automated method for
creating pharmacophore models from
experimentally determined structure data,
e.g., publicly available from the
Brookhaven Protein Databank (PDB). In a
first step, known algorithms were
implemented and improved to extract
small-molecule ligands from the PDB
including assignment of hybridization
states and bond orders. Second, from the
interactions of the interpreted ligands
with relevant surrounding amino acids,
pharmacophore models reflecting functional
interactions like H-bonds or ionic
transfer interactions were created. These
models can be used for screening molecular
databases for similar modes of actions on
the one hand, or for screening one single
compound for potential side-effects
(reversed screening) on the other hand.
The implementation was done using the ilib
framework, which also formed the basis of
the software tool Comb(i)Gen, a
fragment-based virtual combinatorial
library generation program enabling the
user to obtain in silico compound
collections with high drug-likeness.},
keywords = {natural-products
drug design
library},
ISSN = {0033-4545},
DOI = {10.1351/Pac200476050991},
url = {Go to ISI://WOS:000222693700012
http://www.degruyter.com/view/j/pac.2004.76.issue-5/pac200476050991/pac200476050991.xml
http://www.degruyter.com/dg/viewarticle.fullcontentlink:pdfeventlink/$002fj$002fpac.2004.76.issue-5$002fpac200476050991$002fpac200476050991.pdf?t:ac= j$002fpac.2004.76.issue-5$002fpac200476050991$002fpac200476050991.xml},
year = {2004},
type = {Journal Article}
}
x
Virtual combinatorial chemistry and in silico screening: Efficient tools for lead structure discovery?
In this article, an overview of the most common ligand-based in silico screening techniques is given together with an example on the recent successful application of combined use of pharmacophore modeling, database mining, and biological assays. Additionally, a new approach for structure-based high-throughput pharmacophore model generation is presented. The LigandScout program contains an automated method for creating pharmacophore models from experimentally determined structure data, e.g., publicly available from the Brookhaven Protein Databank (PDB). In a first step, known algorithms were implemented and improved to extract small-molecule ligands from the PDB including assignment of hybridization states and bond orders. Second, from the interactions of the interpreted ligands with relevant surrounding amino acids, pharmacophore models reflecting functional interactions like H-bonds or ionic transfer interactions were created. These models can be used for screening molecular databases for similar modes of actions on the one hand, or for screening one single compound for potential side-effects (reversed screening) on the other hand. The implementation was done using the ilib framework, which also formed the basis of the software tool Comb(i)Gen, a fragment-based virtual combinatorial library generation program enabling the user to obtain in silico compound collections with high drug-likeness.
Book chapters
D. Schaller, S. Pach, M. Bermudez and G. Wolber. Exploiting water dynamics for pharmacophore screening, In: Protein-Ligand Interactions and Drug Design, F. Ballante, editor, Springer, ISBN: 1064-3745, pp. 227-238, 2021.
Links: [Publisher]
[show BibTeX]
[show abstract]
x
@inbook{RN304,
author = {Schaller, David and Pach, Szymon and
Bermudez, Marcel and Wolber, Gerhard},
title = {Exploiting water dynamics for
pharmacophore screening},
booktitle = {Protein-Ligand Interactions and Drug
Design},
editor = {Ballante, Flavio},
series = {Methods in Molecular Biology},
publisher = {Springer},
volume = {2266},
pages = {227-238},
abstract = {Three-dimensional pharmacophore models
have been proven extremely valuable in
exploring novel chemical space through
virtual screening. However, traditional
pharmacophore-based approaches need ligand
information and rely on static snapshots
of highly dynamic systems. In this
chapter, we describe PyRod, a novel tool
to generate three-dimensional
pharmacophore models based on water traces
of a molecular dynamics simulation of an
apo-protein.The protocol described herein
was successfully applied for the discovery
of novel drug-like inhibitors of West Nile
virus NS2B-NS3 protease. By using this
recent example, we highlight the key steps
of the generation and validation of
PyRod-derived pharmacophore models and
their application for virtual screening.},
ISBN = {1064-3745},
DOI = {10.1007/978-1-0716-1209-5_13},
url = {https://link.springer.com/protocol/10.1007%2F978-1-0716-1209-5_13
https://link.springer.com/content/pdf/10.1007%2F978-1-0716-1209-5_13.pdf},
year = {2021},
type = {Book Section}
}
x
Exploiting water dynamics for pharmacophore screening
Three-dimensional pharmacophore models have been proven extremely valuable in exploring novel chemical space through virtual screening. However, traditional pharmacophore-based approaches need ligand information and rely on static snapshots of highly dynamic systems. In this chapter, we describe PyRod, a novel tool to generate three-dimensional pharmacophore models based on water traces of a molecular dynamics simulation of an apo-protein.The protocol described herein was successfully applied for the discovery of novel drug-like inhibitors of West Nile virus NS2B-NS3 protease. By using this recent example, we highlight the key steps of the generation and validation of PyRod-derived pharmacophore models and their application for virtual screening.
M. Dumitrascuta, M. Bermudez, S. Ballet, G. Wolber and M. Spetea. Mechanistic understanding of peptide analogues, dalda, [Dmt1]DALDA, and KGOP01, binding to the µ opioid receptor, In: Opioids and their receptors - Present and emerging concepts in opioid drug discovery, M. Spetea and H. Schmidhammer, editors, MDPI, Basel, Switzerland, ISBN: 978-3-03650-046-1, pp. 99-110, 2020.
Links: [Publisher]
[show BibTeX]
[show abstract]
x
@inbook{RN302,
author = {Dumitrascuta, M. and Bermudez, M. and
Ballet, S. and Wolber, G. and Spetea, M.},
title = {Mechanistic understanding of peptide
analogues, dalda, [Dmt1]DALDA, and KGOP01,
binding to the µ opioid receptor},
booktitle = {Opioids and their receptors - Present and
emerging concepts in opioid drug
discovery},
editor = {Spetea, Mariana and Schmidhammer,
Helmut},
publisher = {MDPI},
address = {Basel, Switzerland},
edition = {2020/05/06},
pages = {99-110},
abstract = {The mu opioid receptor (MOR) is the
primary target for analgesia of endogenous
opioid peptides, alkaloids, synthetic
small molecules with diverse scaffolds,
and peptidomimetics. Peptide-based opioids
are viewed as potential analgesics with
reduced side effects and have received
constant scientific interest over the
years. This study focuses on three potent
peptide and peptidomimetic MOR agonists,
DALDA, [Dmt(1)]DALDA, and KGOP01, and the
prototypical peptide MOR agonist DAMGO. We
present the first molecular modeling study
and structure-activity relationships aided
by in vitro assays and molecular docking
of the opioid peptide analogues, in order
to gain insight into their mode of binding
to the MOR. In vitro binding and
functional assays revealed the same rank
order with KGOP01 [Dmt(1)]DALDA DAMGO
DALDA for both binding and MOR
activation. Using molecular docking at the
MOR and three-dimensional interaction
pattern analysis, we have rationalized the
experimental outcomes and highlighted key
amino acid residues responsible for
agonist binding to the MOR. The Dmt (2 ',6
'-dimethyl-L-Tyr) moiety of [Dmt(1)]DALDA
and KGOP01 was found to represent the
driving force for their high potency and
agonist activity at the MOR. These
findings contribute to a deeper
understanding of MOR function and flexible
peptide ligand-MOR interactions, that are
of significant relevance for the future
design of opioid peptide-based
analgesics.},
keywords = {mu opioid receptor opioid peptides and
peptidomimetics damgo dalda [dmt(1)]dalda
kgop01 binding molecular docking
structure-activity relationships in-vitro
potent pharmacology
h-dmt-d-arg-phe-lys-nh2 activation ligands
agonist},
ISBN = {978-3-03650-046-1},
DOI = {10.3390/books978-3-03650-047-8 },
url = {https://www.mdpi.com/books/pdfview/book/3230},
year = {2020},
type = {Book Section}
}
x
Mechanistic understanding of peptide analogues, dalda, [Dmt1]DALDA, and KGOP01, binding to the µ opioid receptor
The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt(1)]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure-activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt(1)]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2 ',6 '-dimethyl-L-Tyr) moiety of [Dmt(1)]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand-MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.
T. Seidel, G. Wolber and M. S. Murgueitio. Pharmacophore perception and applications, In: Applied Chemoinformatics: Achievements and Future Opportunities, J. Gasteiger and T. Engel, editors, , pp. 259-282, 2018. [show BibTeX] x @inbook{RN195, author = {Seidel, Thomas and Wolber, Gerhard and Murgueitio, Manuela S.}, title = {Pharmacophore perception and applications}, booktitle = {Applied Chemoinformatics: Achievements and Future Opportunities}, editor = {Gasteiger, Johann and Engel, Thomas}, pages = {259-282}, year = {2018}, type = {Book Section} }
G. Wolber and W. Sippl. Pharmacophore identification and pseudo-receptor modelling, In: The Practice of Medicinal Chemistry (4th edition), C. G. Wermuth and D. Rognan, editors, Elsevier Ltd, Philadelphia, PA, USA, pp. 489-507, 2015.
Links: [Publisher]
[show BibTeX]
x
@inbook{RN144,
author = {Wolber, G. and Sippl, W.},
title = {Pharmacophore identification and
pseudo-receptor modelling},
booktitle = {The Practice of Medicinal Chemistry (4th
edition)},
editor = {Wermuth, C. G. and Rognan, D.},
publisher = {Elsevier Ltd},
address = {Philadelphia, PA, USA},
pages = {489-507},
keywords = {methods review},
url = {https://www.elsevier.com/books/the-practice-of-medicinal-chemistry/wermuth/978-0-12-417205-0},
year = {2015},
type = {Book Section}
}
G. Wolber and J. Rollinger. Virtual screening and target fishing for natural products using 3D pharmacophores, In: Computational Chemogenomics, E. Jacoby, editor, Pan Stanford Publishing Pte Ltd, Singapore, Malaysia, ISBN: 978-981-4411-39-4, pp. 117-139, 2013.
Links: [Publisher]
[show BibTeX]
x
@inbook{RN141,
author = {Wolber, G. and Rollinger, J.M.},
title = {Virtual screening and target fishing for
natural products using 3D pharmacophores},
booktitle = {Computational Chemogenomics},
editor = {Jacoby, E.},
publisher = {Pan Stanford Publishing Pte Ltd},
address = {Singapore, Malaysia},
pages = {117-139},
ISBN = {978-981-4411-39-4},
DOI = {10.1201/b15631},
url = {http://www.crcnetbase.com/doi/book/10.1201/b15631
https://s3-euw1-ap-pe-ws4-capi2-distribution-p.s3.eu-west-1.amazonaws.com/books/9780429072642/HUBPMP/9780429072642_googleScholarPDF.pdf?response-content-disposition= attachment%3B%20filename%3D%229780429072642_googlepreview.pdf%22&response-content-type=application%2Fpdf&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20210219T123003Z&X-Amz-SignedHeaders=host&X-Amz-Expires=604799&X-Amz-Credential=AKIAQFVOSJ57SSJPZ65S%2F20210219%2Feu-west-1%2Fs3%2Faws4_request&X-Amz-Signature=327fd95516ca09611b52e1da2c6b96f5307533f6d4d2e9610f00dbd873156b77},
year = {2013},
type = {Book Section}
}
J. M. Rollinger and G. Wolber. Computational approaches for the discovery of natural lead structures, In: Bioactive Compounds from Natural Sources, 2nd edition, C. Tringali, editor, CRC Press, London, United Kingdom, ISBN: 1439822298, pp. 97-132, 2011.
Links: [Publisher]
[show BibTeX]
x
@inbook{RN140,
author = {Rollinger, J. M. and Wolber, G.},
title = {Computational approaches for the
discovery of natural lead structures},
booktitle = {Bioactive Compounds from Natural Sources,
2nd edition},
editor = {Tringali, C. },
publisher = {CRC Press},
address = {London, United Kingdom},
pages = {97-132},
ISBN = {1439822298},
DOI = {10.1201/b11196},
url = {http://www.crcnetbase.com/doi/book/10.1201/b11196
https://s3-euw1-ap-pe-ws4-capi2-distribution-p.s3.eu-west-1.amazonaws.com/books/9780429107252/HUBPMP/9780429107252_googleScholarPDF.pdf?response-content-disposition= attachment%3B%20filename%3D%229780429107252_googlepreview.pdf%22&response-content-type=application%2Fpdf&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20210219T122917Z&X-Amz-SignedHeaders=host&X-Amz-Expires=604799&X-Amz-Credential=AKIAQFVOSJ57SSJPZ65S%2F20210219%2Feu-west-1%2Fs3%2Faws4_request&X-Amz-Signature=1f54777ca91d9df336293b2d0195caeb5a3c39048e095e5274c58da2705155e9},
year = {2011},
type = {Book Section}
}
C. Laggner, G. Wolber, J. Kirchmair, S. D. and L. T.. Pharmacophore-based virtual screening in drug discovery, In: Chemoinformatics: An approach to virtual screening, A. Varnek and A. Tropsha, editors, Royal Society of Chemistry, Cambridge, United Kingdom, ISBN: 978-0-85404-144-2, pp. 76-119, 2008.
Links: [Publisher]
[show BibTeX]
x
@inbook{RN139,
author = {Laggner, C. and Wolber, G. and Kirchmair,
J. and Schuster D. and T., Langer},
title = {Pharmacophore-based virtual screening in
drug discovery},
booktitle = {Chemoinformatics: An approach to virtual
screening},
editor = {Varnek, A. and Tropsha, A.},
publisher = {Royal Society of Chemistry},
address = {Cambridge, United Kingdom},
pages = {76-119},
ISBN = {978-0-85404-144-2},
DOI = {10.1039/9781847558879},
url = {http://pubs.rsc.org/en/Content/eBook/978-0-85404-144-2#!divbookcontent},
year = {2008},
type = {Book Section}
}
A. A. Dornhofer, M. Biely, G. Wolber and T. Langer. A novel 2D depiction method using breadth-first ordering and an adapted 2D force field, In: QSAR and Molecular Modelling in Rational Design of Bioactive Molecules, E. Aki Sener and I. Yalcin, editors, Computer Aided Drug Design & Development Society, Ankara, Turkey, ISBN: 975-00782-0-9, pp. 421ff., 2006. [show BibTeX] x @inbook{RN135, author = {Dornhofer, A. A. and Biely, M. and Wolber, G. and Langer, T.}, title = {A novel 2D depiction method using breadth-first ordering and an adapted 2D force field}, booktitle = {QSAR and Molecular Modelling in Rational Design of Bioactive Molecules}, editor = {Aki Sener, E. and Yalcin, I.}, publisher = {Computer Aided Drug Design & Development Society}, address = {Ankara, Turkey}, pages = {421ff.}, ISBN = {975-00782-0-9}, year = {2006}, type = {Book Section} }
T. Langer and G. Wolber. Extracting pharmacophores from bio-active molecules, In: Virtual ADMET assessment in target Selection and maturation, B. Testa and L. Turski, editors, IOS Press, Amsterdam, Netherlands, ISBN: 978-1-58603-703-1, pp. 133-150, 2006. [show BibTeX] x @inbook{RN153, author = {Langer, T. and Wolber, G.}, title = {Extracting pharmacophores from bio-active molecules}, booktitle = {Virtual ADMET assessment in target Selection and maturation}, editor = {Testa, B. and Turski, L.}, series = { Solvay pharmaceutical conferences}, publisher = {IOS Press, Amsterdam, Netherlands}, pages = {133-150}, ISBN = {978-1-58603-703-1}, year = {2006}, type = {Book Section} }
G. Wolber, M. Biely and T. Langer. De novo drug design using randomized virtual chemistry and property filtering: a heuristic approach, In: QSAR and Molecular Modelling in Rational Design of Bioactive Molecules, E. Aki Sener and I. Yalcin, editors, Computer Aided Drug Design & Development Society, Ankara, Turkey, ISBN: 975-00782-0-9, pp. , 2006. [show BibTeX] x @inbook{RN136, author = {Wolber, Gerhard and Biely, Martin and Langer, Thierry}, title = {De novo drug design using randomized virtual chemistry and property filtering: a heuristic approach}, booktitle = {QSAR and Molecular Modelling in Rational Design of Bioactive Molecules}, editor = {Aki Sener, E. and Yalcin, I.}, publisher = {Computer Aided Drug Design & Development Society}, address = {Ankara, Turkey}, ISBN = {975-00782-0-9}, year = {2006}, type = {Book Section} }
G. Wolber and R. Kosara. Pharmacophores from macromolecular complexes with LigandScout, In: Pharmacophores and pharmacophore searches, T. Langer and R. Hofmann, editors, Wiley-VCH, Weinheim, Germany, ISBN: 3-527-31250-1, pp. 131-148, 2006.
Links: [Publisher]
[show BibTeX]
x
@inbook{RN138,
author = {Wolber, G. and Kosara, R.},
title = {Pharmacophores from macromolecular
complexes with LigandScout},
booktitle = {Pharmacophores and pharmacophore
searches},
editor = {Langer, T. and Hofmann, R.},
publisher = {Wiley-VCH},
address = {Weinheim, Germany},
volume = {32},
pages = {131-148},
keywords = {software},
ISBN = {3-527-31250-1},
url = {http://eu.wiley.com/WileyCDA/WileyTitle/productCd-3527608729.html},
year = {2006},
type = {Book Section}
}
G. Wolber. Structure-based Pharmacophores From Protein-Bound Ligands (German: Strukturbasierte Pharmacophore aus proteingebundenen Liganden), In: Lecture notes in informatics (LNI) D-5, D. Wagner, editor, Bonner Koellen Verlag, Bonn-Buschdorf, Germany, ISBN: 3-88579-409-8, pp. 209-218, 2004. [show BibTeX] x @inbook{RN134, author = {Wolber, G.}, title = {Structure-based Pharmacophores From Protein-Bound Ligands (German: Strukturbasierte Pharmacophore aus proteingebundenen Liganden)}, booktitle = {Lecture notes in informatics (LNI) D-5}, editor = {Wagner, D. }, publisher = {Bonner Koellen Verlag}, address = {Bonn-Buschdorf, Germany}, pages = {209-218}, ISBN = {3-88579-409-8}, year = {2004}, type = {Book Section} }
T. Langer and G. Wolber. CombiGen: A novel software package for the rapid generation of virtual combinatorial libraries, In: Rational Approaches to Drug Design, H. Höltje and W. Sippl, editors, Prous Science, Barcelona, Spain, ISBN: 84-8124-176-8, pp. 390-399, 2001. [show BibTeX] x @inbook{RN133, author = {Langer, Thierry and Wolber, Gerhard}, title = {CombiGen: A novel software package for the rapid generation of virtual combinatorial libraries}, booktitle = {Rational Approaches to Drug Design}, editor = {Höltje, H.-D and Sippl, W.}, publisher = {Prous Science}, address = {Barcelona, Spain}, pages = {390-399}, ISBN = { 84-8124-176-8}, year = {2001}, type = {Book Section} }
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