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|Title:||Synergism of virtual screening and medicinal chemistry: Identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1|
|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|
|Appears in Collections:||Staff Publications|
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