A systematic computational drug repurposing approach identifies gamma-oryzanol and azilsartan as promising plasmepsin II inhibitors for malaria treatment

The emergence of drug-resistant Plasmodium falciparum strains has created an urgent need for novel antimalarial agents, with Plasmepsin II (PM2), a critical haemoglobin-degrading enzyme in the malaria parasite, representing an attractive therapeutic target for drug repurposing efforts. Using a systematic computational drug repurposing approach that integrated molecular docking, 100 ns molecular dynamics simulations, and MM-GBSA binding energy calculations, we screened 3500 FDA-approved compounds against PM2, evaluating the stability and binding mechanisms of lead compounds through comprehensive structural analysis and interaction profiling. Our screening revealed that Gamma-Oryzanol and Azilsartan emerged as the most promising PM2 inhibitors. Despite comparable initial docking scores ranging from -8.1 to -9.7 kcal/mol, these compounds demonstrated superior binding stability during molecular dynamics simulations, achieving MM-GBSA binding energies of -54.26 ± 2.92 kcal/mol and -45.32 ± 3.87 kcal/mol, respectively. Both compounds maintained stable binding within the catalytic pocket throughout the simulation period, forming consistent interactions with critical residues including the catalytic dyad (Asp34, Asp214), flap region (Lys72-Phe85), and proline-rich loop (Ile290-Pro297). The strong correlation observed between hydrogen bond persistence, binding energy contributions, and overall stability metrics provided robust validation of their inhibitory potential. These findings suggest that Gamma-Oryzanol and Azilsartan represent promising candidates for PM2 inhibition through mechanisms involving direct substrate access blocking or restriction of conformational changes required for catalysis. As FDA-approved agents with established safety profiles, these compounds offer accelerated development potential as antimalarial therapeutics. The integration of multiple computational methods demonstrates significant value in drug repurposing efforts against critical pathogen targets, warranting immediate in vitro validation and further structural optimization studies.