Deciphering the inhibitory activity of flavonoids against Plasmodium falciparum proteases through molecular docking, drug-likeness and pharmacokinetic studies

Abstract Despite the available synthetic antimalarial drugs, malaria remains a significant global health disease with millions of cases reported annually. This study investigated the inhibitory activity of flavonoids against Plasmodium proteases (Plasmodium falciparum Plasmepsin II (PfPlm II); Plasmodium falciparum subtilisin-like protease 2 (PfSUB2); and Plasmodium falciparum Falcipain-2 (PfFP2) using in silico models. One hundred and seven (107) flavonoids were subjected to molecular docking studies against PfPlm II, PfSUB2, and PfFP2. Thereafter, the most active compounds were subjected to in silico drug-likeness and pharmacokinetic assays. Findings from the molecular docking study indicated that 8 compounds showed higher binding energies against the selected malaria target proteases when compared to pepstatin A, phenylmethylsulfonyl fluoride (PMSF) and trans-epoxysuccinyl-L-leucylamido(4-guanidino)butane (E-64) (reference drug with binding energy of -12.8, -5.9 and − 5.8 Kcal/mol for PfPlm II, PfSUB2, and PfFP2, respectively). The binding energies of these flavonoids against Plasmodium proteases range from − 9.8 to -7.0 Kcal/mol for PfPlm II, -8.5 to -5.6 Kcal/mol for PfSUB2 and − 10.7 to -7.0 Kcal/mol for PfFP2. In addition, robinin and narirutin displayed higher binding energies for the two Plasmodium proteases, while 6 other flavonoids either had higher binding affinity for one of these proteins compared other compounds. The drug-likeness results of the 8 compounds indicated that baicalin violated only 2 Lipinski’s rule of five. The other 7 flavonoids obeyed at least three criteria of this rule. Notwithstanding, these compounds displayed no toxic effects and low absorption rates as observed from the predicted absorption, distribution, metabolism, elimination and toxicity (ADMET) and toxicity analysis. Overall, these flavonoids could serve as potential candidates for developing therapeutic agents in the management of malaria.