Penicillium-Derived Inhibitors of Lactate Dehydrogenase (PfLDH): A Computational Approach for Novel Antimalarial Therapy Development.

Malaria remains a major global health challenge, necessitating the discovery of novel therapeutic agents. This study investigates secondary metabolites from spp. as potential inhibitors of lactate dehydrogenase (PfLDH), a critical enzyme in the parasite's glycolytic pathway. A curated library of -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 strains.