(627f) Molecular Modeling of Antimalarial Drug Activity in Suppressing Hematin Crystal Growth

Malaria remains a significant public health challenge. As antimalarial drugs become less effective due to drug and vector resistance, the ongoing burden of malaria demands the development of new drugs. When the malaria parasite consumes hemoglobin in the host’s red blood cell cytosol, it produces hematin as a byproduct. To prevent the toxicity of free hematin buildup, the parasite sequesters it into harmless β-hematin crystals. Antimalarial drugs are posited to act by inhibiting this crystallization pathway. These drugs may hinder crystal growth through step pinning and kink blocking mechanisms, or both. Step pinners bind to steps, while kink blockers prevent solute access at kinks. Some drugs exhibit dual-action behavior by combining these mechanisms. In this study, we combine experiments, molecular docking simulations, and analytical models to interrogate the growth and inhibition of β-hematin crystals. Specifically, we examine the binding behavior of 6 known antimalarials to various crystal surface sites (faces, kinks, and steps) to characterize how they interact with the crystals and their modes of action (step pinners vs. kink blockers). We also present a model to describe the competitive binding between drugs molecules and hematin. Our findings reveal that hematin crystals grow by spreading of individual molecular rows and not by full unit cells. All drugs are found to have an affinity for all sites, but preferential binding is observed to the grooves of c-face. Lastly, our results indicate that all drugs function as dual-action inhibitors, highlighting their effectiveness in crystal inhibition. The broader implications of the results are discussed in the context of developing novel therapeutic agents for malaria.