The Exploration of Hydromorphone Analogues as Potential Antimalarial Agents

Abstract

Introduction: Malaria, a life-threatening disease caused by Plasmodium parasites, still poses a severe threat to public health safety in Africa, South America, and Asia. It is transmitted via Anopheles mosquito bites and has been reported to be a major cause of toddler mortalities in these regions. Due to its mutation-mediated drug resistance and continued spread of the disease, there still exists a need to investigate and discover more effective antimalarial drugs. Hydromorphone is a semi-synthetic opioid agonist and a hydrogenated ketone of morphine with pain-relieving qualities and serves as a second-line drug to morphine in the treatment of both chronic and acute pain. Methods: High-throughput virtual screen of hydromorphone analogues was done using Autodock Vina. The results of protein-ligand complexes were visualised using Discovery Studio Visualizer, and ligands with the best binding scores were used to perform MD simulations using GROMACS software. Results: The promising candidate derivatives included analogues of both hydromorphone and mor-phine with hydroxy and ether constituents in the benzene ring. The best performing docking scores were carried forward to molecular dynamics using the GROMACS software. The ligands showed stability during these simulations and thus serve as promising inhibitors of DXR. Discussion: During molecular docking, all ligands docked in chain A did not bind in the active site. This may be due to the small binding pocket in chain A. For chain B, eight ligands (four with NADPH and without NADPH) with the best docking score were further taken for molecular dynamics simu-lations, and their RMSDs were calculated after molecular dynamics, which all showed stability in the binding pocket. Conclusion: The Hydromorphone derivatives explored in this study showed promising results when interacting with chain B of PfDXR (4gae) protein. other: N/A