Malaria caused by Plasmodium falciparum continues to be a major health burden, and the parasite depends on hemoglobin digestion for its survival inside human red blood cells. The enzymes operating in this pathway plasmepsins, falcipains, aminopeptidases and serine proteases play specific roles in the stepwise breakdown of hemoglobin, and therefore serve as important points for drug intervention. In this work, twelve proteases with experimentally solved structures were prepared using standard protein-refinement procedures, binding sites were identified, and a library of 326 compounds was docked using Glide-SP. The screened molecules included approved antimalarial drugs, repurposable candidates and selected marine natural products with antimalarial and antiprotozoal activity. Plasmepsin IV produced the strongest binding scores, with WEHI-842 and saquinavir showing tight fitting in the active site. HIV-protease inhibitors and diamidines also showed good interactions with several proteases, which is consistent with earlier reports of their antimalarial effects. Cysteine proteases and metallo-aminopeptidases gave moderate binding for a few compounds like pentamidine, aliskiren and carvedilol. Some large natural molecules also showed notable pocket fitting, suggesting scope for future exploration. The results indicate that structure-based screening can help narrow down promising molecules before lab testing and can support repurposing ideas when the mechanism of binding overlaps with the parasite targets. Since ligand–protein interactions mainly depend on shape, charge and other physical forces, a few drugs originally made for different diseases can also show affinity towards parasite enzymes. This study provides a set of candidates that can be taken forward to biochemical assays and parasite-culture studies to check their actual antimalarial activity.
A Tue, study studied this question.