Premium
Virtual Screening for Selective Allosteric mGluR1 Antagonists and Structure–Activity Relationship Investigations for Coumarine Derivatives
Author(s) -
Noeske Tobias,
Jirgensons Aigars,
Starchenkovs Igors,
Renner Steffen,
Jaunzeme Ieva,
Trifanova Dina,
Hechenberger Mirko,
Bauer Tanja,
Kauss Valerjans,
Parsons Christopher G.,
Schneider Gisbert,
Weil Tanja
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700151
Subject(s) - metabotropic glutamate receptor 1 , allosteric regulation , virtual screening , metabotropic glutamate receptor , pharmacophore , chemistry , allosteric modulator , metabotropic glutamate receptor 5 , homology modeling , stereochemistry , ligand (biochemistry) , antagonist , receptor , combinatorial chemistry , biochemistry , glutamate receptor , enzyme
A virtual screening study towards novel noncompetitive antagonists of the metabotropic glutamate receptor 1 (mGluR1) is described. Alignment‐free topological pharmacophore descriptors (CATS) were used to encode the screening compounds. All virtual hits were characterized with respect to their allosteric antagonistic effect on mGluR1 in both functional and binding assays. Exceptionally high hit rates of up to 26 % were achieved, confirming the applicability of this virtual screening concept. Most of the compounds were found to be moderately active, however, one potent and subtype selective mGluR1 antagonist, 13 (IC 50 : 0.362 μ M , SEM ±0.031; K i : 0.753 μ M , SEM ±0.048), based on a coumarine scaffold was discovered. In a following activity optimization program a series of coumarine derivatives was synthesized. This led to the discovery of potent ( 60 , IC 50 : 0.058 μ M , SEM ±0.008; K i : 0.293 μ M , SEM ±0.022) and subtype selective (rmGluR5 IC 50 : 28.6 μ M ) mGluR1 antagonists. From our homology model of mGluR1 we derived a potential binding mode within the allosteric transmembrane region. Potential interacting patterns are proposed considering the difference of the binding pockets between rat and human receptors. The study demonstrates the applicability of ligand‐based virtual screening for noncompetitive antagonists of a G‐protein coupled receptor, resulting in novel, potent, and selective agents.