Structural Insights into Plasmepsin Inhibition by Phenolic Compounds from African Mistletoe (Tapinanthus globiferus) Parasitizing Vitex Doniana

In Nigeria, Tapinathus globiferus is used in traditional medicine in the managements of hypertension, diabetes, ulcers, infections, and skin itching, while aiding childbirth. In Europe, it addresses circulatory/respiratory issues, cancer, epilepsy, and acts as a nervous tonic. Malaria remains a devastating parasitic disease, with Plasmodium falciparum resistance to current therapies necessitating new drug targets. Plasmepsins I and II (Plm-I/II), aspartic proteases critical for hemoglobin degradation in the parasite’s life cycle, represent promising candidates. This study investigated four Tapinanthus globiferus-derived compounds—catechin (Y10), catechin-3-gallate (Y11), 4-methoxyphenyl acryl aldehyde (Y12), and 4-hydroxy-3-methoxy acryl aldehyde (Y13)—for their Plm-I (PDB: 3QS1) and Plm-II (PDB: 1LF3) inhibitory potential using molecular docking and ADMET profiling. Molecular docking revealed binding affinities ranging from −5.0 to −6.7 kcal/mol (Plm-I) and −5.6 to −8.4 kcal/mol (Plm-II). Catechin-3-gallate (Y11) exhibited the highest affinity for both enzymes (−6.7 and −8.4 kcal/mol, respectively), surpassing other ligands though lower than native co-crystallized inhibitors. Notably, Y11 formed a critical hydrogen bond with Asp214 (Plm-II catalytic dyad), explaining its enhanced binding. ADMET predictions indicated favorable drug-likeness: all compounds followed Lipinski’s rule, with catechin (Y10) classified as least toxic (Class VI). These findings highlight T. globiferus metabolites, particularly catechin-3-gallate, as promising plasmepsin inhibitors. The strong affinity and low toxicity profiles underscore their potential as antimalarial leads. Further in vitro and in vivo validation is warranted to advance their therapeutic development.