Bioactive Molecules Against Malarial Dihydroorotate Dehydrogenase: An in silico Approach

Malaria, caused by Plasmodium falciparum, remains a major cause of mortality among children in African countries. Due to the parasite's resistance against existing malarial drugs, there is a contemporary need for the exploration of potent compounds possessing anti-malarial properties. Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH) is one of the promising targets (PDB ID: 6GJG) for treating malaria. This study aims to incorporate computational approaches to explore potent phytochemicals with reported biological activity as inhibitors of pfDHODH and to investigate the molecular-level details. The results showed that acetylmontrifoline, retusin, montrifoline, ealamine D, rhamnazin, and canaliculin stand out as potential inhibitors of the enzyme with binding affinities of -11.308 kcal/mol, -11.251 kcal/mol, -11.221 kcal/mol, -10.938 kcal/mol, -10.920 kcal/mol, and -10.827 kcal/mol, respectively, better than that of the native ligand with -9.873 kcal/mol. The adducts exhibited significant geometrical stability, with good RMSD of ligands below 5 Å from 200 ns molecular dynamics simulation, and sustained thermodynamic stability from the MMPBSA method. All other geometrical evaluators also supported the stability of the complexes. The pharmacokinetics and pharmacodynamics predicted moderate drug-likeness, and the hit candidates could be proposed for further in vivo and in vitro experiments to validate the computational results.