Computational Studies of Mitragynine Analogue Binding at the Human Mu-Opioid Receptor
The mu-opioid receptor (MOR) is a well-characterized G-protein coupled receptor and a major target of opioid pharmaceuticals. Opioid agonists exert their effects by MOR binding through two major downstream pathways: G-protein signaling and beta-arrestin signaling. The design of MOR agonists that favor or exclusively activate G-protein signaling may provide a new class of pharmaceuticals for pain relief with improved side-effect profiles. Mitragynine is the active compound of the herbal supplement kratom. Its distinct molecular structure and potential G-protein bias has gained increasing attention. Mitragynine analogues were designed and tested in-silico using several computer-aided drug design approaches. A homology model of the human MOR was constructed in Swiss-Model using a murine MOR crystal structure (PDB: 5C1M). A compound library of mitragynine analogues was iteratively constructed and passed through the SwissADME web tool to predict pharmacokinetics before molecular docking. Analogues with predicted access to the central nervous system (CNS) underwent water-solvent geometry optimization in Spartan and were simulated in the human MOR active site by a flexible ligand-rigid receptor docking calculation in AutoDock Vina. Analogues with MOR-activity comparable to mitragynine were retained for simulation in a flexible ligand-flexible receptor calculation for improved accuracy. Notably, results revealed several CNS-accessible analogues with similar in-silico activity at the human MOR compared to existing biased and mitragynine-analogue agonists. This computational study provides direction for the rational drug design of mitragynine toward G-protein biased agonists by identifying several analogues with potential activity at the human MOR. These findings prompt follow-up pharmacological testing to establish if these lead compounds act as agonists and possess a bias for G-protein signaling.
https://drive.google.com/file/d/1dt9ynqzAJmL3FtJVFqJZSkX_OdebGa9j/view?usp=sharing
Very interesting research! Your research poster looks really organized and easy to follow! Great work!
Hi James,
Your research is very interesting and well-organized. I feel that your presentation could have been strengthened by adding a audio or video narration. Great work!