title: Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors.
abstract: Available crystal structures of opioid receptors provide a high-resolution picture of ligand binding at the primary ("orthosteric") site, that is, the site targeted by endogenous ligands. Recently, positive allosteric modulators of opioid receptors have also been discovered, but their modes of binding and action remain unknown. Here, we use a metadynamics-based strategy to efficiently sample the binding process of a recently discovered positive allosteric modulator of the δ-opioid receptor, BMS-986187, in the presence of the orthosteric agonist SNC-80, and with the receptor embedded in an explicit lipid-water environment. The dynamics of BMS-986187 were enhanced by biasing the potential acting on the ligand-receptor distance and ligand-receptor interaction contacts. Representative lowest-energy structures from the reconstructed free-energy landscape revealed two alternative ligand binding poses at an allosteric site delineated by transmembrane (TM) helices TM1, TM2, and TM7, with some participation of TM6. Mutations of amino acid residues at these proposed allosteric sites were found to either affect the binding of BMS-986187 or its ability to modulate the affinity and/or efficacy of SNC-80. Taken together, these combined experimental and computational studies provide the first atomic-level insight into the modulation of opioid receptor binding and signaling by allosteric modulators.
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors: Yi
authors: Y
authors: Shang
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors: Holly R
authors: HR
authors: Yeatman
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors: Davide
authors: D
authors: Provasi
authors: GPCR Lead Discovery & Optimization, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492 United States.
authors: Andrew
authors: A
authors: Alt
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors: Arthur
authors: A
authors: Christopoulos
authors: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors: Meritxell
authors: M
authors: Canals
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors: Marta
authors: M
authors: Filizola
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000495:Allosteric Site / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D044004:Xanthones / Q000494:pharmacology*
chemical_list: C000616653:BMS-986187; D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D044004:Xanthones; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide