title: Consensus 3D model of μ-opioid receptor ligand efficacy based on a quantitative Conformationally Sampled Pharmacophore.
abstract: Despite being studied for over 30 years, a consensus structure-activity relationship (SAR) that encompasses the full range peptidic and nonpeptidic μ-opioid receptor ligands is still not available. To achieve a consensus SAR the Conformationally Sampled Pharmacophore (CSP) method was applied to develop a predictive model of the efficacy of μ-opioid receptor ligands. Emphasis was placed on predicting the efficacy of a wide range of agonists, partial agonists, and antagonists as well as understanding their mode of interaction with the receptor. Inclusion of all accessible conformations of each ligand, a central feature of the CSP method, enabled structural features between diverse μ-opioid receptor ligands that dictate efficacy to be identified. The models were validated against a diverse collection of peptidic and nonpeptidic ligands, including benzomorphans, fentanyl (4-anilinopiperidine), methadone (3,3-diphenylpropylamines), etonitazene (benzimidazole derivatives), funaltrexamine (C6-substituted 4,5-epoxymorphinan), and herkinorin. The model predicts (1) that interactions of ligands with the B site, as with the 19-alkyl substituents of oripavines, modulate the extent of agonism; (2) that agonists with long N-substituents, as with fentanyl and N-phenethylnormorphine, can bind in an orientation such that the N substitutent interacts with the B site that also allows the basic N-receptor Asp interaction essential for agonism; and (3) that the μ agonist herkinorin, that lacks a basic nitrogen, binds to the receptor in a manner similar to the traditional opioids via interactions mediated by water or a ion. Importantly, the proposed CSP model can be reconciled with previously published SAR models for the μ receptor.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Shim
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
mesh_terms: D008024:Ligands; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013797:Thebaine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D008024:Ligands; D010455:Peptides; D017450:Receptors, Opioid, mu; D013797:Thebaine; C005283:oripavine