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

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 molecul

SUBMITTER: Orgovan Z 

PROVIDER: S-EPMC6825653 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature