In-silico study of the bioactive compounds of Blighia sapida koenig revealed a novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitor for malaria

In response to the challenge of drug-resistant malaria, this study investigated the antimalarial potential of B. sapida ethanolic leaf extract using an in silico approach. Gas chromatography-mass spectrometry (GC-MS) analysis was performed to identify compounds present in the extract. Molecular docking and dynamics simulations were conducted to assess interactions and stability between selected lead compounds and the target protein PfDHODH using AutoDock Vina and GROMACS, respectively. A total of twenty-one compounds were identified and the three most abundant were D-Fructose 3-O-methyl- (21.02%), phytol (20.77%), and hexadecanoic acid ethyl ester (13.11%). Complementary in silico docking analyses demonstrated interactions between all 21 compounds and PfDHODH. Among them, three compounds demonstrated strong binding affinities (- 8.1 to - 10.0 kcal/mol) comparative to the positive control (N-(2,2-diphenylethyl)-4-hydroxy-1,2,5-thiadiazole-3-carboxamide) with binding energy - 8.9 kcal/mol. Linoleic acid ethyl ester, octadecanoic acid ethyl ester, and 2-methyl-6-(4-methylenecyclohex-2-en-1-yl)hept-2-en-4-one displayed favorable drug-likeness and ADMET profiles. Among these, 2-methyl-6-(4-methylenecyclohex-2-en-1-yl)hept-2-en-4-one emerged as the most stable inhibitor (RMSD = 0.12, RMSF = 0.10, ROG = 2.02, SASA = 171.90), followed by octadecanoic acid ethyl ester (RMSD = 0.13, RMSF = 0.11, ROG = 2.02, SASA = 172.31). These results highlight the promising antimalarial potential of B. sapida and provide insight into its bioactive constituents.