Computational Analysis of Luteolin, Apigenin and Their Derivatives from Allophylus africanus as Potential Inhibitors of Plasmepsin II a Malaria Target

Malaria is a life-threatening disease prevalent in tropical and subtropical regions. It remains a critical global health challenge, particularly in sub-Saharan Africa where Plasmodium falciparum parasite species is rampant. With the rise of drug-resistant strains, the urgency for novel and effective antimalarial therapies has never been greater. In the absence of a highly effective vaccine, chemotherapy continues to be the frontline defense against malaria. One promising avenue for therapeutic intervention is Plasmepsin II (PMII) an essential aspartic protease involved in hemoglobin degradation within the parasite’s digestive vacuole. Targeting PM II has the potential to disrupt the parasite’s lifecycle, making it a compelling focus for the development of next-generation antimalarial drugs, crucial in the fight against resistant strains. In this study, the interactions of luteolin, apigenin, and their glycoside derivatives from Allophylus africanus with PMII was explored through computational methods. Using molecular docking, molecular dynamics (MD) simulations, and free energy calculations, the binding affinities, structural stability, and conformational changes induced by these compounds were evaluated. The docking results revealed that luteolin derivatives, particularly 1 luteolin-7-O-glucoside and luteolin-3’,7-di-O-glucoside, exhibited strong binding affinities, with binding energies of −9.1 and −9.5 kcal/mol, respectively. These interactions were driven by enhanced hydrogen bonding and hydrophobic interactions with key residues such as Asp34 and Asp214 in the active site of PMI. Apigenin derivatives, including apigenin-6,8-di-C-hexoside, also demonstrated significant binding affinity with a binding energy of −10.2 kcal/mol. The overall binding energy with MMPBSA further reinforced these findings with apigenin 8-C-hexoside showing the strongest binding free energy of (−86.646 kJ/mol), driven by significant van der Waals stabilization. Luteolin-3’,7-di-O-glucoside and apigenin-6,8-di-C-hexoside also exhibited strong binding free energies of −57.506 kJ/mol and −79.591 kJ/mol, respectively, indicating their potential as effective inhibitors. Free energy surface (FES) revealed that luteolin and derivatives binding favours an open-state conformation of the PMI flap, while apigenin derivatives induce multiple conformational states reflecting a more flexible interaction. This study demonstrates the potential of apigenin 8-C-hexoside, luteolin-3’,7-di-O-glucoside, and apigenin-6,8-di-C-hexoside as effective agents against the malaria target. These compounds could serve as promising candidates for developing new antimalarial drugs. Nevertheless, further experimental research is required to validate their efficacy.