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Abstract <p>Malaria remains a critical global health challenge due to rising <i>Plasmodium falciparum</i> resistance. Natural products are a rich source of novel antimalarials; extracts of <i>Salacia debilis</i> (SD) have shown potent antiplasmodial effects. Here, three <i>S. debilis</i>–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 <i>P. falciparum</i> enoylacyl carrier protein reductase (PfENR), an enzyme in the parasite’s type&#xa0;II fatty acid biosynthesis pathway absent in humans, as the primary target, with binding affinities of − 8.50 to − 8.90&#xa0;kcal/mol. Extended 500&#xa0;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 <i>S. debilis</i> 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.</p> Graphical abstract <p></p>

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Computational elucidation of Plasmodium falciparum enoyl-ACP reductase inhibition by Salacia debilis compounds: adaptive ligand binding drives antimalarial activity

  • 期刊论文

  • 发表日期：

    2025年8月27日

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  • Prince Manu,
  • Muntawakilu Padiga Seidu,
  • Alice Adomako,
  • Caleb Kusi Asamoah,
  • Ophelia Duodu,
  • Akyana Britwum,
  • Michael Konney Laryea,
  • Godfred Darko,
  • Lawrence Sheringham Borquaye

摘要

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.

Graphical abstract