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

Abstract Mitragynine pseudoindoxyl (MP), a derivative of mitragynine, is one of the prominent alkaloids derived from Mitragyna speciosa, commonly known as kratom or ketum. It exhibits considerable potential for various pharmacological applications [1]. Nevertheless, the molecular interactions between MP and cellular membranes remain poorly understood [2]. In this study, molecular dynamics (MD) simulations were employed to investigate the behavior of MP compounds within lipid bilayers, aiming to elucidate their mechanisms of membrane interaction. A model system comprising three MP molecules embedded in a fully hydrated dipalmitoylphosphatidylcholine (DPPC) lipid bilayer was simulated using the GROMACS program for a duration of 100 ns. The simulation results show that MP diffuses into the lipid bilayer region as early as ~53 ns for a single molecule and ~60 ns for a pair of MP molecules. The molecules preferentially position themselves beneath the lipid head groups. Hydrogen bonds were formed between MP and the carbonyl and phosphate groups of the lipid bilayer, as well as water molecules that entered from the aqueous region. These findings highlight the hydrophobic nature of MP, facilitating its integration into lipid bilayers. By enhancing our understanding of MP's molecular behavior and membrane interactions, this study contributes valuable insights for the development of therapeutic strategies targeting membrane-associated processes