MOLECULAR DYNAMICS SIMULATION OF MITRAGYNINE INTERACTIONS WITH DOPAMINE D1 AND D2 RECEPTORS: ASSESSING PSYCHOACTIVE EFFECTS AND THERAPEUTIC POTENTIAL

Abstract

The therapeutic and psychoactive properties of mitragynine, the primary alkaloid in Mitragyna speciosa (kratom), are well documented, particularly in pain therapeutics. However, the molecular interactions between mitragynine and the D1 and D2 dopamine receptors—essential targets for pain modulation and therapeutic interventions in conditions like schizophrenia and depression—remain poorly understood. We employed molecular dynamics simulations to investigate the binding interactions of mitragynine and 7-hydroxymitragynine at D1 and D2 dopamine receptors. Root mean square deviation (RMSD) analysis demonstrated that mitragynine stabilized at approximately 0.3 nm for D1 and 0.4 nm for D2, indicating substantial structural stability. In contrast, 7-hydroxymitragynine exhibited increased RMSD values of roughly 0.45 nm for D1 and 0.50 nm for D2, indicating greater structural flexibility and receptor activation potential. Furthermore, MM-PBSA analyses evaluating binding free energies revealed that mitragynine possessed thermodynamically favorable interactions at D1 (-6.46 kcal/mol) and D2 (-6.10 kcal/mol). Conversely, 7-hydroxymitragynine had a destabilizing positive total energy change at D1 (0.81 kcal/mol) despite demonstrating a comparable binding affinity at D2 (-6.02 kcal/mol). These quantitative findings demonstrate that mitragynine exhibits a significantly higher stabilizing affinity for both D1 and D2 receptors compared to 7-hydroxymitragynine. This structural and thermodynamic energy landscape highlights how mitragynine may be therapeutically beneficial for disorders associated with dopamine dysregulation, providing a foundation for future in vitro cellular assays and in vivo models.