A Study of Mitragynine Interactions with DPPC Lipid Bilayer using Molecular Dynamics Simulations

Abstract

Mitragynine, an alkaloid derived from the psychotropic plant Mitragyna speciosa, commonly known as kratom or ketum, is prevalent in Thailand and Malaysia. As the most abundant alkaloid present in kratom (1), mitragynine possesses significant pharmacological properties, for instance analgesic effect (2). Furthermore, Malaysia is currently revising on the Kratom’s Poison Act 1952 toward legalizing kratom for medical use (3). However, despite its widespread use and potential therapeutic applications, the molecular interactions of mitragynine with cellular membranes remain poorly understood. In this study, we employed molecular dynamics (MD) simulations to investigate the behavior of mitragynine compounds interacting with membrane lipid bilayers. By elucidating the mechanism of mitragynine's interaction with lipid membranes, our research aims to shed light on its bioavailability, cellular uptake, and potential pharmacological implications. A model system comprising three mitragynine molecules embedded in a fully hydrated dipalmitoylphosphatidylcholine (DPPC) lipid bilayer was simulated using the GROMACS program for a duration of 100 ns. Our findings indicate that mitragynine rapidly diffuses into the lipid bilayer region, with penetration occurring as early as ~23 ns. During the simulation, we observed both single and paired mitragynine molecules entering the lipid bilayer, where they preferentially positioned themselves below the lipid head groups, forming hydrogen bonds with the carbonyl and phosphate groups, as well as with water molecules. Collectively, our results demonstrate the hydrophobic nature of mitragynine, enabling its interaction with and penetration into the lipid bilayer. This study contributes to a better understanding of molecular behavior of mitragynine, providing valuable insights for future drug design and development targeting cellular membranes.