title: Structure-based discovery of allosteric modulators of two related class B G-protein-coupled receptors.
abstract: Despite the availability of X-ray crystal structure data for several members of the G-protein-coupled receptor (GPCR) superfamily, structure-based discovery of GPCR ligands has been exclusively restricted to class A (rhodopsin-like) receptors. Herein we report the identification, by a docking-based virtual screening approach, of noncompetitive ligands for two related class B (secretin-like) GPCRs: the glucagon receptor (GLR) and the glucagon-like peptide 1 receptor (GLP-1R). Starting from a knowledge-based three-dimensional model of the GLR, a database of 1.9 million commercially available drug-like compounds was screened for chemical similarity to existing GLR noncompetitive antagonists and docked to the transmembrane cavity of the GLR; 23 compounds were then selected based on protein-ligand interaction fingerprints, and were then purchased and evaluated for in vitro binding to GLR and modulation of glucagon-induced cAMP release. Two of the 23 compounds inhibited the effect of glucagon in a dose-dependent manner, with one inhibitor exhibiting the same potency as L-168 049, a reference noncompetitive GLR antagonist, in a whole-cell-based functional assay. Interestingly, one virtual hit that was inactive at the GLR was shown to bind to GLP-1R and potentiate the response to the endogenous GLP-1 ligand.
authors: Structural Chemogenomics Group, Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS-UdS, 74 route du Rhin, 67400 Illkirch, France.
authors: Chris
authors: C
authors: de Graaf
authors: Chantal
authors: C
authors: Rein
authors: David
authors: D
authors: Piwnica
authors: Fabrizio
authors: F
authors: Giordanetto
authors: Didier
authors: D
authors: Rognan
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001665:Binding Sites; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018019:Receptors, Corticotropin-Releasing Hormone; D018027:Receptors, Glucagon