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Curr Opin Struct Biol. 2016 Dec;41:83-89. doi: 10.1016/j.sbi.2016.06.008. Epub 2016 Jun 22.

G-protein coupled receptors: advances in simulation and drug discovery.

Author information

  • 1Howard 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.
  • 2Howard 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.

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.

PMID:
27344006
PMCID:
PMC5154880
[Available on 2017-12-01]
DOI:
10.1016/j.sbi.2016.06.008
[PubMed - in process]
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