The role of water and protein flexibility in the structure-based virtual screening of allosteric GPCR modulators: an mGlu5 receptor case study

Zoltán Orgován,György G Ferenczy,György M Keserű

doi:10.1007/s10822-019-00224-w

Abstract

Stabilizing unique receptor conformations, allosteric modulators of G-protein coupled receptors (GPCRs) might open novel treatment options due to their new pharmacological action, their enhanced specificity and selectivity in both binding and signaling. Ligand binding occurs at intrahelical allosteric sites and involves significant induced fit effects that include conformational changes in the local protein environment and water networks. Based on the analysis of available crystal structures of metabotropic glutamate receptor 5 (mGlu5) we investigated these effects in the binding of mGlu5 receptor negative allosteric modulators. A large set of retrospective virtual screens revealed that the use of multiple protein structures and the inclusion of selected water molecules improves virtual screening performance compared to conventional docking strategies. The role of water molecules and protein flexibility in ligand binding can be taken into account efficiently by the proposed docking protocol that provided reasonable enrichment of true positives. This protocol is expected to be useful also for identifying intrahelical allosteric modulators for other GPCR targets.

Highlights

Structure-based virtual screening is an established computational technique for the identification of chemical starting points in drug discovery programs [1]
Mavoglurant and M-MPEP share a common acetylenic linker, this moiety does not perfectly overlay in the two crystal structures and the growing vectors of the headgroups have different orientation for the two ligands [9]. These findings clearly show that modelling of ligand binding is challenging even for a chemotype with available X-ray structures
Our analysis focused on the virtual screening performance of m Glu5 receptor protein structures derived from complexes with negative allosteric modulators having varying scaffolds

Summary

Introduction

Structure-based virtual screening is an established computational technique for the identification of chemical starting points in drug discovery programs [1]. Virtual screening allows to select compounds for experimental testing that improves the efficiency of hit finding. Structure-based screening requires atomic resolution protein structures that are available either from experiment or as computational models. Owing to the increasing availability of GPCR X-ray structures these important class of proteins are extensively and successfully used in structure-based virtual screening campaigns [2]. GPCR virtual screen aims to identify ligands binding in the intrahelical orthosteric binding site.

Objectives

Results

Conclusion