Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery

Abstract

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. Some ligands that bind to GPCRs activate different downstream signaling pathways. G protein activation, or β-arrestin biased signaling, involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. β-arrestin biased signaling has become a hot target for structure-based drug discovery. However, challenges include that there are few crystal structures available in the Protein Data Bank and that GPCRs are highly dynamic. Hence, molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators’ interactions with receptors and ligands. Here, we highlight recent MD simulation studies and enhanced sampling methods used to study biased G protein-coupled receptor signaling and their conformational dynamics as well as applications to drug discovery.

Keywords

• GPCRs
• membrane protein
• molecular dynamics
• protein structure
• drug design
• biased-signaling pathway
• allosteric sites