title: G-protein coupled receptors: advances in simulation and drug discovery.
abstract: G-protein coupled receptors (GPCRs), the largest family of human membrane proteins, mediate cellular signaling and represent primary targets of about one third of currently marketed drugs. GPCRs undergo highly dynamic structural transitions during signal transduction, from binding of extracellular ligands to coupling with intracellular effector proteins. Molecular dynamics (MD) simulations have been utilized to investigate GPCR signaling mechanisms (such as pathways of ligand binding and receptor activation/deactivation) and to design novel small-molecule drug candidates. Future research directions point towards modeling cooperative binding of multiple orthosteric and allosteric ligands to GPCRs, GPCR oligomerization and interactions of GPCRs with different intracellular signaling proteins. Through methodological and supercomputing advances, MD simulations will continue to provide important insights into GPCR signaling mechanisms and further facilitate structure-based drug design.
authors.affiliation: Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093, United States; Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, United States. Electronic address: yimiao@ucsd.edu.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093, United States; Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, United States; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States. Electronic address: jmccammon@ucsd.edu.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D017076:Computer-Aided Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled