Computational investigation of minor alkaloids of Mitragyna speciosa Korth leaves as natural opioid analgesics

Mitragynine is the most abundant compound in kratom (Mitragyna speciosa Korth). Furthermore, it is not explicitly mentioned which compound(s) essentially contribute to the opioid activity of this plant. In this work, we identify the compounds that are most responsible for the opioid activity. This study was completed with a comprehensive computational framework consisting of virtual screening, frontier molecular orbital profiling, prediction of ADMET properties, and validated using molecular dynamics simulations for 100 ns. The results showed that the most contributing compounds interacting with each opioid receptor are 9-methoxy-mitralactonine (δ-opioid receptor), isomitraphylline (ƙ-opioid receptor), and mitraphylline (μ-opioid receptor). The ADMET profile indicated that the three compounds were predicted to pass the Lipinski rule of five, having a good lead likeness and being relatively non-toxic. The molecular dynamics results exhibited stable complexes between the three receptors and each compound based on the profiles of RMSD and RMSF during the simulations.