Structure‐Based Discovery of Allosteric Modulators of Two Related Class B G‐Protein‐Coupled Receptors

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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