Speaker
Description
Malaria remains a global health threat causing high mortalities among children under 5 years old in the tropics and sub-tropics. The prevalence of drug-resistant Plasmodium falciparum, underscoring the need for selective new leads. Natural products have long served as a rich source of novel antimalarials and extracts and isolates of Salacia debilis (SD) have shown potent antiplasmodial effects. While the isolates demonstrate incredible antimalarial effect in vivo, understanding their protein targets and possible molecular mechanims is crucial for drug modification and optimization. We examined three SD isolates: SD03 (benzyl 2-methoxybenzoate), SD04 (1,10-dihydroxy-6H-benzo[c]chromen-6-one), and SD05 (8-hydroxy-3,4-dimethoxydibenzo[b,d]furan-1-carboxylic acid), to determine their molecular target, following their antiplasmodial potential. High-throughput virtual screening and molecular docking identified P. falciparum enoyl-ACP reductase (PfENR), a Plasmodium parasite-specific enzyme in type II fatty-acid biosynthesis, as the top candidate with predicted binding energies between –8.50 and –8.90 kcal·mol⁻¹. Extended 500 ns molecular dynamics simulations validated stable, ligand-specific complexes and revealed interaction patterns that engage key catalytic residues (Tyr111, Tyr267, Leu315). These interactions mimic those formed by the benchmark inhibitor triclosan and promote enzyme conformations consistent with inhibition. Computational ADME-T profiling prioritized SD04 as the most promising lead on pharmacokinetic grounds. Together, these results provide a mechanistic rationale for the antiplasmodial activity of S. debilis isolates and support PfENR-directed optimization as a strategy to develop selective and new agents against drug-resistant malaria.