title: Synergism of virtual screening and medicinal chemistry: identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1.
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 IC(50)=0.74+/-0.29 microM). Hit optimization yielded lead structure 16 with an affinity of K(i)=0.024+/-0.001 microM 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.
authors: Merz Pharmaceuticals GmbH, Altenhöfer Allee 3, D-60438 Frankfurt, Germany.
authors: Tobias
authors: T
authors: Noeske
authors: Dina
authors: D
authors: Trifanova
authors: Valerjans
authors: V
authors: Kauss
authors: Steffen
authors: S
authors: Renner
authors: Christopher G
authors: CG
authors: Parsons
authors: Gisbert
authors: G
authors: Schneider
authors: Tanja
authors: T
authors: Weil
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D055808:Drug Discovery; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D054852:Small Molecule Libraries; C104077:metabotropic glutamate receptor type 1