Activation and Drug Design of a Muscarinic G-Protein Coupled Receptor

Abstract

The M2 muscarinic acetylcholine receptor is a key G-protein coupled receptor (GPCR) that regulates the human heart rate and contractile forces of cardiomyocytes, and is thus targeted for treating many heart diseases. Here, we have performed long-timescale accelerated molecular dynamics (aMD) simulations and captured activation of the M2 muscarinic receptor at an atomistic level(1). The receptor activation is characterized by large-scale structural rearrangements of the transmembrane helices and conformational changes in the inter-helical salt bridge and hydrogen bond interactions(1, 2). Furthermore, using the aMD simulation-derived structural ensembles that account for the receptor flexibility, we have mapped the receptor surface for druggable allosteric sites(3) and then targeted the extracellular vestibule for designing allosteric modulators. Retrospective docking of known ligands is first carried out to validate the simulation receptor ensembles, followed by prospective docking to predict new allosteric modulators from the National Cancer Institute (NCI) compound library. The computationally selected compounds will be tested using experimental binding and functional assays, which may allow us to discover selective allosteric drugs of the M2 muscarinic receptor.