Molecular modeling of the interactions of compounds of Irvinga wombulu against dihydrofolate reductase-thymidylate synthase in Plasmodium falciparum towards development of anti-malarial drug.

Abstract

Malaria is a significant global health burden that affects the majority of people in the world. Nigeria still accounts for the highest percentage of the worldwide malaria burden, with 27% of estimated malaria cases and 31% of estimated deaths due to malaria in 2022. While antimalarial effects have been attributed to some active compounds from medicinal plants, no study has been conducted on Irvingia wombulu (IW). Therefore, this study aimed to evaluate the in silico antimalarial activity of some active compounds identified after gas chromatography/mass spectrometry (GC/MS) studies on Irvingia wombolu. The compounds were docked against the anti-malaria target Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) of Plasmodium falciparum with PDB ID 3QGT and their pharmacokinetic properties were also predicted. This was followed by a molecular dynamics (MD) simulation of the protein in complex with the most promising IW compound. The GC-MS result revealed 44 phytoconstituents from IW. The Docking analysis revealed the following best binding energies (kcal/mol): alpha-tocopherol-beta-D-mannoside (-11.289), gamma-tocopherol (- 7.308), and linolenic acid (- 6.822). MD Simulation showed that the selected compound exhibited a stable conformation in the active site of the flexible protein. Pharmacokinetics analysis suggested that the compounds will be orally bio-available when administered. Therefore, these results indicate that these compounds can be considered for experimental validation and further development into antimalarial drugs.