(−)-Mitragynine, a natural alkaloid, is known for its analgesic effects and functions as a G protein-biased ligand of the μ-opioid receptor (μOR). This study examined the structural alterations in the μOR upon binding with (−)-mitragynine, (+)-mitragynine, 7-OH-mitragynine, and morphine using molecular docking and 1 μs classical all-atom molecular dynamics simulations. The μOR showed relatively stable RMSD ranging from 1.6 to 3.2 Å for mitragynine derivatives and morphine during dynamics, though residues 260–280 exhibited notable fluctuations. (−)-Mitragynine formed an average of one hydrogen bond more consistently than the other ligands throughout the simulation period. MM/PBSA calculations suggested that Asp-147 (3.32), Tyr-148 (3.33), Met-151 (3.36), and Trp-293 (6.84) contributed to ligand binding. Asp-147 (3.32) plays a critical role in the formation of a salt bridge and contributes the most to binding all mitragynine derivatives and morphine. All four ligands preferentially interacted with Trp-293 (6.84) in helix-6, highlighting its role in receptor activation and postsignaling activities. A plot of the binding free energy versus the helix-6 tilt angle and the distance between Asp-147 (3.32) and the tertiary nitrogen of the ligand revealed a distinct conformational population at 6 to 10 Å and 90 to 140° tilting of the receptor for morphine compared to mitragynine, which may explain helix-6’s role and salt bridge distance in μOR activation and downstream signaling biases. Our study provides a structural foundation for designing novel μOR ligands as potential new analgesics.
Neupane et al. (Thu,) studied this question.