title: Molecular Docking, Molecular Dynamics, and Structure-Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists.
abstract: Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure-activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3-7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.
authors.affiliation: Computer-Aided Molecular Design (CAMD) Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Noha
authors.affiliation: Opioid Research Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
authors.affiliation: Opioid Research Group, Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria.
authors.forename: Mariana
authors.identifier: 0000-0002-2379-5358
authors.initials: M
authors.lastname: Spetea
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry*; D015195:Drug Design; D008745:Methylation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009019:Morphinans / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D009019:Morphinans; D017450:Receptors, Opioid, mu; D010100:Oxygen
keywords: agonist; ligand binding; molecular docking; morphinan; structure−activity relationships; μ-Opioid receptor