Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bmc.2009.05.072
Title: Synergism of virtual screening and medicinal chemistry: Identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1
Authors: Noeske, T.
Trifanova, D.
Kauss, V.
Renner, S.
Parsons, C.G.
Schneider, G.
Weil, T. 
Keywords: Antagonist
Metabotropic
mGluR1
Self-organizing map
Virtual screening
Issue Date: 1-Aug-2009
Citation: Noeske, T., Trifanova, D., Kauss, V., Renner, S., Parsons, C.G., Schneider, G., Weil, T. (2009-08-01). Synergism of virtual screening and medicinal chemistry: Identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1. Bioorganic and Medicinal Chemistry 17 (15) : 5708-5715. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bmc.2009.05.072
Abstract: We report the identification of novel potent and selective metabotropic glutamate receptor 1 (mGluR1) antagonists by virtual screening and subsequent hit optimization. For ligand-based virtual screening, molecules were represented by a topological pharmacophore descriptor (CATS-2D) and clustered by a self-organizing map (SOM). The most promising compounds were tested in mGluR1 functional and binding assays. We identified a potent chemotype exhibiting selective antagonistic activity at mGluR1 (functional IC50 = 0.74 ± 0.29 μM). Hit optimization yielded lead structure 16 with an affinity of Ki = 0.024 ± 0.001 μM and greater than 1000-fold selectivity for mGluR1 versus mGluR5. Homology-based receptor modelling suggests a binding site compatible with previously reported mutation studies. Our study demonstrates the usefulness of ligand-based virtual screening for scaffold-hopping and rapid lead structure identification in early drug discovery projects. © 2009 Elsevier Ltd. All rights reserved.
Source Title: Bioorganic and Medicinal Chemistry
URI: http://scholarbank.nus.edu.sg/handle/10635/94999
ISSN: 09680896
DOI: 10.1016/j.bmc.2009.05.072
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

22
checked on Sep 19, 2018

WEB OF SCIENCETM
Citations

22
checked on Sep 4, 2018

Page view(s)

34
checked on Jun 1, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.