title: Activation and Allosteric Modulation of Human μ Opioid Receptor in Molecular Dynamics.
abstract: Allosteric protein modulation has gained increasing attention in drug design. Its application as a mechanism of action could bring forth safer and more effective medicines. Targeting opioid receptors with allosteric modulators can result in better treatment of pain, depression, and respiratory and immune disorders. In this work we use recent reports on negative modulators of μ opioid receptor as a starting point for identification of allosteric sites and mechanisms of opioid receptor modulation using homology modeling and docking and molecular dynamics studies. An allosteric binding site description is presented. Results suggest a shared binding region for lipophilic allosteric ligands, reveal possible differences in the modulation mechanism between cannabinoids and salvinorin A, and show ambiguous properties of the latter. Also, they emphasize the importance of native-like environment in molecular dynamics simulations and uncover relationships between modulator and orthosteric ligand binding and receptor behavior. Relationships between ligands, transmission switch, and hydrophobic lock are analyzed.
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin , 4A Chodźki St., PL-20093 Lublin, Poland.
authors.forename: Damian
authors.initials: D
authors.lastname: Bartuzi
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin , 4A Chodźki St., PL-20093 Lublin, Poland.|School of Pharmacy, University of Eastern Finland , Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin , 4A Chodźki St., PL-20093 Lublin, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Matosiuk
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000495:Allosteric Site / Q000187:drug effects; D045785:Diterpenes, Clerodane / Q000737:chemistry / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009020:Morphine / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D027544:Salvia / Q000737:chemistry
chemical_list: C502982:9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho(2,1-c)pyran-7-carboxylic acid methyl ester; D045785:Diterpenes, Clerodane; D005663:Furans; D008024:Ligands; D011753:Pyrones; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; C090499:salvinorin A