Exploring Plant-Derived Natural Products Against Plasmodium falciparum Malaria Causative Agent by Targeting Protein Kinase 5: Insights Into Computational Approaches.

Malaria continues to pose a significant public health threat, particularly across African nations, where Plasmodium falciparum accounts for over 90% of global malaria-related deaths. The progression and survival of P. falciparum are heavily reliant on key proteins, including protein kinase 5 (PfPK5), which is essential for the parasite's cell division and survival. Due to its pivotal role, PfPK5 represents a promising target for antimalarial drug development. This study employed cheminformatics approaches to identify potential PfPK5 inhibitors derived from bioactive compounds in Nigerian plants with known antimalarial properties. A total of 196 compounds from 14 plant species were assessed for drug-likeness, and the drug-like candidates were docked into the active site of PfPK5. The binding free energies of the three top-scoring compounds were subsequently evaluated alongside their pharmacokinetic and toxicological properties. Thirteen compounds demonstrated strong binding affinities, with docking scores ranging from -6.075 to -10.072 kcal/mol, surpassing the performance of artemisinin, the reference drug, which showed a docking score of -5.613 kcal/mol. Among these, marmesin, cryptolepinone, and lecanoric acid exhibited the most favorable interactions, with binding free energies of -48.73, -43.46, and -29.95 kcal/mol, respectively, compared to -20.19 kcal/mol for artemisinin. Molecular dynamics simulations over 100 ns confirmed the stability of these interactions. Furthermore, the identified compounds demonstrated favorable pharmacokinetic and safety profiles. In conclusion, this study identifies marmesin, cryptolepinone, and lecanoric acid as promising candidates for further computational and experimental investigations aimed at developing novel antimalarial therapies targeting PfPK5.