Unlocking the Enigmas of Plasmodium Aspartyl Protease in Antimalarial Therapy: Flap Region Dynamics and Enzyme Repression of Non-Food Vacuole Using Molecular Dynamics Simulations.

Abstract

Introduction: Plasmepsin X (PMX) is a crucial aspartyl protease that prevents malaria parasite invasion and egresses into erythrocytes, making it a potential multiple-stage therapeutic target.

Methods: Recent research has led to the identification of UCB7362, an orally active PMX inhibitor with experimental antimalarial efficiency. In this report, we investigate the binding mechanism of UCB736 to the nonfood vacuole PMX. Most importantly, the detailed molecular description of the binding mechanism of UCB7362 to PMX sites that are not fully explored in the literature. We also examined the influence of UCB7363 binding on the flap region dynamics of PMX, a crucial dynamic event needed for protease enzyme activity and significant impacts on drug binding.

Results: Molecular dynamics simulations and binding affinity calculations were utilized in this work. Interestingly, the catalytic dyad (Asp266 and Asp456) was found to be the most contributing residues towards the binding of UCB7362, underscoring the significance of the pair in the catalytic activity of the enzyme. Post- MD analyses revealed that UCB7362 binding caused disruption in the "twist motion" of the protease and subsequently forced the flap regions to coil in to tightly wrap the inhibitor, reducing the surface area and creating a compact binding architecture for the ligand.

Conclusion: Finally, we developed a pharmacophore model based on UCB7362 to offer recommendations for rational drug design of optimized antimalarial drug candidates.