Molecular Docking, Molecular Dynamics, and Structure-Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent ?-Opioid Receptor Agonists.

ABSTRACT: Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via ?-opioid receptor (?-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 ?-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 ?-OR and interaction mechanisms. The structure of activated ?-OR provides an essential model for how ligand/?-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these ?-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the ?-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/?-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5?-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 ?-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

SUBMITTER: Noha SM 

PROVIDER: S-EPMC5481819 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature