title: Virtual screening for selective allosteric mGluR1 antagonists and structure-activity relationship investigations for coumarine derivatives.
abstract: 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 microM, SEM +/-0.031; K(i): 0.753 microM, 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 microM, SEM +/-0.008; K(i): 0.293 microM, SEM +/-0.022) and subtype selective (rmGluR5 IC(50): 28.6 microM) 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.
authors.affiliation: Merz Pharmaceuticals GmbH, Altenhöfer Allee 3, 60438 Frankfurt am Main, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Noeske
authors.forename: Aigars
authors.initials: A
authors.lastname: Jirgensons
authors.forename: Igors
authors.initials: I
authors.lastname: Starchenkovs
authors.forename: Steffen
authors.initials: S
authors.lastname: Renner
authors.forename: Ieva
authors.initials: I
authors.lastname: Jaunzeme
authors.forename: Dina
authors.initials: D
authors.lastname: Trifanova
authors.forename: Mirko
authors.initials: M
authors.lastname: Hechenberger
authors.forename: Tanja
authors.initials: T
authors.lastname: Bauer
authors.forename: Valerjans
authors.initials: V
authors.lastname: Kauss
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Parsons
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Tanja
authors.initials: T
authors.lastname: Weil
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C030123:coumarin