Scrutiny of Mitragynin and derivatives with analgesic potential using Mep and ligand-MOR interaction

Abstract

Mitragynine and derivatives with analgesic activity were scrutinized to unravel key structural features necessary for biological activities and interactions with the m-opioid receptor (MOR). Molecular electrostatic potential (MEP) scrutiny showed the anionic and phenolic sites, as well as the hydrophobic region of opioids, important for analgesic activity, susceptible to electrophilic attack by a biological target and that the presence of bulky substituents at C9 and C7 can hinder analgesia, through steric hindrance, and increase the positive MEP region in the phenolic site. Scrutiny of the interaction with the MOR showed the most active opioids, in general, having the tertiary N atom of the anionic site closest to the C atom from the COOH of the Asp147 residue of the MOR. Furthermore, opioids present hydrogen bond interactions between the H atom from the OCH3 of the phenolic site with the phenolic O atom from the OH of the Tyr148 residue of the MOR and of the H atom from the OH of this residue with the O atom from the OCH3 of the hydrophobic region. The accumulated insights led to the design of new derivatives and the identification of two (2) of them as promising derivatives for synthesis and biological assays.