In silico analysis of azadirachtin and its analogs on dihydrofolate reductase of Plasmodium species

Abstract

The occurrence of mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes has led to the emergence of resistance to antifolate antimalarials worldwide. Azadirachtin, a secondary metabolite is an antimalarial constituent of Azadirachta indica (Neem tree) that similarly acts on dihydrofolate reductase. The study aimed to conduct in silico analysis of the inhibitory potential of azadirachtin-derived compound analogs against DHFR in Plasmodium species using techniques such as molecular docking, and drug-likeness using Lipinski rule of 5, prediction of adsorption, distribution, metabolism, and excretion (ADME). The docking analysis was conducted using azadirachtin as a template and twenty-nine ligands of zinc drug-like analogs as well as two clinical drugs, proguanil, and pyrimethamine as positive control ligands. Molecular docking results predicted that the ligands inhibit dihydrofolate reductase enzyme (2BL9) out of which ten ligands were focused based on their binding energy scores. It was observed that azadirachtin yielded seven analogs that showed binding energies higher than azadirachtin at values -10.1, -9.7, -9.5, -9.5, -9.2, and -9.1 kcal/mol except for zinc72320527 which had the same binding energy as azadirachtin whereas the reference ligands, azadirachtin, proguanil, and pyrimethamine showed high affinity to 2BL9 with binding energies of -8.8, -7.7 and -7.3 kcal/mol respectively. They obeyed the Lipinski rule of five and from ADME data, gastrointestinal absorption of the molecules was high except for zinc72320527. The results of the study show that the analogs have potential use as antimalarial agents and could be synthesized for oral formulation with further modifications.