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.

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

“…The results reported here are comparable to those from other similar works [19][20][21][22] which showed that GPCR modeling [23][24][25][26][27][28][29][30][31] in the absence of a crystal structure can be a valid replacement [32][33][34][35][36][37][38][39] for structural and functional exploration of GPCR receptors, and for the discovery [21,[40][41][42][43], VS [44][45][46][47][48][49][50][51][52] and optimisation [23,53] of their ligands.…”

Structure-Based Ligand Discovery Targeting Orthosteric and Allosteric Pockets of Dopamine Receptors

“…Discovery of allosteric compounds is considered a much more challenging problem, with only a few examples of putative allosteric hits arising from VLS campaigns (de Graaf et al, 2011b;Mysinger et al, 2012). In this study, we specifically aimed at expanding large-scale VLS applications beyond orthosteric sites by 1) developing an optimized D3R APO model of the full binding pocket with allosteric extension, and 2) developing an ND, no inhibition of 10 nM dopamine detected.…”

Construction and Retrospective Validation of Structure-Based Virtual Screening Protocols to Identify Potent Ligands for Human Adrenergic Beta-2 Receptor

“…The successful three dimensional (3D) structure characterization through crystallography of ADRB2 bound to its antagonist carazolol (Cherezov et al, 2007) was followed by 3D characterization of some other GPCRs Jaakola et al, 2008;Shimamura et al, 2011;Wacker et al, 2010;Wu et al, 2010), which have offered opportunities to construct, validate and perform SBVS to discover novel potent ligands for a particular GPCR both on the crystal structures (Carlsson et al, 2010;Katritch et al, 2010;Kolb et al, 2009;Yakar and Akten, 2014) and homology models (Carlsson et al, 2011;de Graaf et al, 2011 b ;Istyastono et al, 2011 b ;Sirci et al, 2012;Tarcsay et al, 2013). Solely used of SBVS approaches on Histamine H1 Receptor (HRH1) crystal structure in the recent virtual screening campaigns showed extraordinary results, both retrospectively and prospectively .…”