title: How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways.
abstract: Substantial attention has recently been devoted to G protein-biased agonism of the μ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management. Specifically, we carried out multimicrosecond, all-atom molecular dynamics (MD) simulations of the binding of this ligand to the activated MOR crystal structure. Analysis of >50 μs of these MD simulations provides insights into the energetically preferred binding pathway of TRV-130 and its stable pose at the orthosteric binding site of MOR. Information transfer from the TRV-130 binding pocket to the intracellular region of the receptor was also analyzed, and was compared to a similar analysis carried out on the receptor bound to the classical unbiased agonist morphine. Taken together, these studies lead to a series of testable hypotheses of ligand-receptor interactions that are expected to inform the structure-based design of improved opioid analgesics.
authors: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors: Sebastian
authors: S
authors: Schneider
authors: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors: Davide
authors: D
authors: Provasi
authors: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors: Marta
authors: M
authors: Filizola
mesh_terms: D000596:Amino Acids / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D003460:Crystallization; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D000072417:Protein Domains; D055550:Protein Stability; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism
chemical_list: C586842:((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine; D000596:Amino Acids; D008024:Ligands; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D013876:Thiophenes