Identification of Phytochemicals Inhibiting PfCDPK-1, PfCDPK-2, PfCDPK-4, LDH and Hexokinase of Plasmodium falciparum
Malaria remains a major global health challenge, exacerbated by the emergence of drug-resistant Plasmodium falciparum strains. To address this, novel therapeutic strategies targeting essential parasite proteins are urgently needed. In this study, we employed a computational drug discovery approach to identify potential inhibitors against five key P. falciparum proteins: cyclin-dependent kinases (PfCDK1, PfCDK2, PfCDK4), hexokinase, and lactate dehydrogenase (PfLDH). These proteins play critical roles in parasite cell cycle regulation and energy metabolism, making them attractive targets for selective inhibition. Phytochemicals were sourced from the LOTUS database—a curated repository of natural products derived from plants. Ligands were initially screened using Lipinski’s Rule of Five (Ro5), drug-likeness criteria, and toxicity filters including mutagenicity, tumorigenicity, and irritability. Non-toxic candidates were subjected to molecular docking to evaluate binding affinities and interaction patterns with the target proteins. Molecular mechanics simulations were subsequently employed to assess the structural stability and energy profiles of the protein-ligand complexes. In addition, in silico ADMET profiling was performed to evaluate pharmacokinetic properties and safety parameters. Several compounds exhibited strong binding affinities and favorable interaction energies, particularly against PfCDK4 and PfLDH. Our findings show that the integration of natural product databases with computational screening and mechanics-based modeling proved effective in identifying promising antimalarial candidates, warranting further experimental validation.