Enhanced Simulations and Drug Discovery of a Muscarinic G-Protein-Coupled Receptor

Abstract

G-protein-coupled receptors (GPCRs) represent primary targets of about one third of currently marketed drugs. However, GPCR drug discovery has suffered from major challenges, including the highly flexible nature of the receptors and the toxicity of agonist or antagonist drugs that are designed to bind the conserved “orthosteric” site. Here, we have performed all-atom enhanced simulations using the robust Gaussian accelerated molecular dynamics (GaMD) method to investigate the ligand-dependent structural dynamics of the M2 muscarinic GPCR. The GaMD simulations revealed distinct structural flexibility and free energy profiles that depict graded activation of the GPCR. Both dissociation and binding of an orthosteric ligand were captured in a single all-atom GPCR simulation(1). In addition, we have implemented a unique structure-based approach to design allosteric modulators as selective drug leads of the M2 muscarinic receptor. Through iterative molecular docking and experimental testing, half of our 38 computationally selected lead compounds were validated as effective allosteric modulators of the M2 receptor. Our method successfully identified both positive and negative allosteric modulators of the M2 muscarinic receptor with unprecedented chemical diversity and outstanding potential for further structure-activity relationship studies(2). This approach shall be of wide applicability for drug discovery of many other GPCRs(3).