Abstract

Malaria remains a major global health challenge, necessitating the discovery of novel therapeutic agents. This study investigates secondary metabolites from Penicillium spp. as potential inhibitors of Plasmodium falciparum lactate dehydrogenase (PfLDH), a critical enzyme in the parasite’s glycolytic pathway. A curated library of Penicillium-derived compounds underwent drug-likeness and toxicity screening, resulting in the identification of 42 viable candidates. Molecular docking simulations revealed three promising compounds—Penicilactone B, Penicillimide, and Penicillisocoumarin A—with binding affinities exceeding those of the positive controls, NADH, and pyruvate. Among these, Penicilactone B exhibited the strongest binding affinity (−8.71 kcal/mol) and the lowest inhibitory constant (414.77 nM). Molecular dynamics simulations confirmed the stability of these compounds within the PfLDH binding pocket over a 200-ns trajectory, with Penicilactone B demonstrating the most stable interactions. Off-target predictions suggested minimal interaction with human lactate dehydrogenase, indicating a potentially favorable safety profile. Penicilactone B emerged as the most promising candidate due to its molecular stability, efficient binding, and favorable solvent interactions. Penicillisocoumarin A also showed potential, supported by its pharmacokinetic properties and safety indicators. These findings highlight the potential of penicillium-derived secondary metabolites as a promising source for novel antimalarial therapies targeting PfLDH. Future research should focus on experimental validation, pharmacokinetic optimization, and efficacy testing against diverse Plasmodium strains.