Indra Vikram Singh, , Anup Kumar
The rapid emergence of Plasmodium falciparum malaria resistant to currently available antifolate antimalarial drugs has added a further serious concern, making the provision of malarial treatment increasingly difficult and costly. So, there is an urgent need to search for new antimalarials which are both effective and cheap, to combat the emerging drug resistant parasites. The dihydrofolate reductase (DHFR) domain of P. falciparum bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a validated target for antifolate antimalarials. Inhibitors of DHFR disrupted the folate biosynthesis pathway. In this study, Molecular modeling techniques will perform to design pyrimethamine derivatives of Plasmodium falciparum dihydrofolate reductase (PfDHFR) and candidates were shortlisted on the basis of docking scores and binding affinity. The docking results of Pyrimethamine and their twenty six derivatives with PfDHFR predicted that compound CID 10476801 had the lowest docking energy (-11.48 kcal/mol) and stabilized by hydrogen bonds and could be a drug candidate, which inhibit PfDHFR structure. Yet pharmacological studies have to confirm it.
Keywords: Pyrimethamine, PfDHFR, Malaria, AutoDock, Plasmodium falciparum.