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.

Synthesis, Pharmacology, and Molecular Docking Studies on 6-Desoxo-N-methylmorphinans as Potent μ-Opioid Receptor Agonists

“…Accounting for pharmacophore models inferred within LigandScout, 20 receptor side chains in putative contact with the bound ligands are depicted in Figure 2 and listed in Table 2 . In line with our recent findings from molecular docking, 8 the aromatic ring of targeted morphinans was deduced to be embedded by hydrophobic residues (e.g., M151, V236, I296, and V300), which are responsible for hydrophobic interactions ( Table 2 and Figures 2 ). The participation of the phenolic hydroxyl group at position 3 in a water-mediated hydrogen-bonding network with H297 was shown by all ligands.…”

“… 5 , 7 Our recent molecular docking and molecular dynamics simulations study 8 using the active structure of the MOR (PDB code 5C1M) 9 in combination with structure–activity relationships (SAR) on N -methylmorphinan-6-ones revealed the subtle interplay between substituents at positions 5 and 14 in the morphinan scaffold in the ligand–MOR interaction by enabling identification of key structural elements that determine their distinct pharmacological profiles. 8 …”

A Computational Approach to Identify a Potential Alternative Drug With Its Positive Impact Toward PMP22

“…For this reason, powerful computational tools with high accuracy have been a great boon in identifying the probable compounds that could help in the field of drug discovery Noha et al, 2017]. This increases the demand for identification of novel personalized drug compounds with better efficacy.…”

Simulating Protein Structure to Support Clinical Decisions: Predicting the Ligand Specific Impact of Genomic Variation on Opioid Binding

“…Molecular docking is a common approach to modelling drug:target interactions, ranking various binding modes and predicting the binding a nity of a protein-ligand pair. Docking simulations have revealed information about receptor binding site conformations (10), and recently, identi ed novel drugs for the mu-opioid receptor (11)(12)(13). However, molecular docking studies focus primarily on the wild-type receptor, failing to capture the effect of functional variants on receptor binding a nity.…”