Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening.

Wanjing Guo,Dehua Yang,Antao Dai,Márton Vass,Ming-Wei Wang,Qingtong Zhou,Wenqing Shui,Xiaoqing Cai,Chris de Graaf,Suwen Zhao

doi:10.3390/biom11070929

Abstract

Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.

Highlights

G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology [1,2] and are one of the most successful therapeutic targets with over 500 approved drugs [3,4]
Focused on an extra-helical allosteric site where the negative allosteric modulators (NAMs) PF-0637222 and positive allosteric modulators (PAMs) compound 2 bind, we developed a new virtual screening strategy to discover allosteric modulators at the lipid interface of GPCR transmembrane domain (TMD): Structure-based virtual screening (SBVS) takes the lipid interactions into consideration and ligand-based virtual screening (LBVS) retains the specific residue contacts involved in the allosteric site
After analyzing the reported allosteric modulators, we screened a focused library with loosely defined physicochemical properties that were filtered as described above [34]

Summary

Introduction

G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology [1,2] and are one of the most successful therapeutic targets with over 500 approved drugs [3,4]. To mediate transmembrane signal transduction, GPCR has the following two spatially distant but conformationally linked regions: the extracellular agonist-binding site and the intracellular transducer binding site [5,6]. Besides the orthosteric sites where the endogenous agonists bind, recent structural and pharmacological studies highlight the fact that ligands can bind spatially and topologically to distinct (allosteric) sites on receptors and modulate GPCRmediated signaling simultaneously through conformational cooperativity [6,7,8,9,10,11,12]. As a successful therapeutic target for type 2 diabetes and obesity, many peptidic analogs of GLP-1 are on the market

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Conclusion