Abstract
ABSTRACT: Malaria remains a critical global health challenge due to rising Plasmodium falciparum resistance. Natural products are a rich source of novel antimalarials; extracts of Salacia debilis (SD) have shown potent antiplasmodial effects. Here, three S. debilis-derived 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) were investigated to identify their molecular target. Highthroughput screening and molecular docking revealed P. falciparum enoylacyl carrier protein reductase (PfENR), an enzyme in the parasite's type II fatty acid biosynthesis pathway absent in humans, as the primary target, with binding affinities of - 8.50 to - 8.90 kcal/mol. Extended 500 ns molecular dynamics (MD) simulations confirmed stable, conformation-specific ligand-enzyme complexes. The isolates' interaction footprints closely match those of triclosan, a benchmark PfENR inhibitor, by engaging key active site residues (Tyr111, Tyr267, Leu315) and trapping the enzyme in inactive states. These results establish a mechanistic basis for the antiplasmodial activity of S. debilis isolates and validate PfENR as a target for selective antimalarial development. SD04 emerged as the lead candidate based on favorable pharmacokinetic predictions, highlighting its potential for structure-guided optimization against drug-resistant malaria. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00413-6.