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.

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