Publication: Antimalarial activity of ellagic acid against plasmodium falciparum proteases by computational approach
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Date
2026-01
Authors
Zaidi, Nur Alya Nabihah Mohd
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Abstract
Malaria is a life-threatening disease caused by Plasmodium falciparum and remains a major global health burden. The malaria parasite survival during its erythrocytic stage critically depends on haemoglobin degradation within its acidic digestive vacuole (DV) by a process mediated by a cascade of proteases. Ellagic acid (EA), a natural polyphenol, has demonstrated promising antimalarial activity, potentially by disrupting the DV function, but its precise molecular targets within this pathway are unknown. This study employed a computational approach to identify and characterise the interaction between EA and key P. falciparum DV proteases involved in haemoglobin catabolism. Ten protease structures were selected based on their critical roles and retrieved from the RCSB Protein Data Bank. Molecular docking simulations were performed using CB-Dock2 server to predict binding affinities and analyse interaction modes. The results revealed that EA exhibited strong binding affinity across multiple protease targets with IC50 value of 1.85 ± 4.57 nM for the 3D7 strain and 1.3 ± 0.1 nM against W2 strains, with the highest predicted affinity observed for the cysteine protease, falcipain 2 with Vina score of -9.7 kcal/mol. Analysis of the falcipain 2-EA complex indicated that binding is stabilised by a synergistic network of hydrogen bonds, hydrophobic interactions and π-stacking within the enzyme’s active site. These findings provide the first molecular evidence positioning falcipain 2 as a potential primary target for EA, elucidating a plausible mechanism for its antimalarial effect through disruption of haemoglobin digestion. This study supports the potential of EA as a novel antimalarial agent in combination therapies and lays a
computational foundation for the rational design of more potent derivatives targeting
falcipain 2