In-Silico Pharmacokinetics Study on the Inhibitory Potentials of the C=O Derivative of Gedunin and Pyrimethamine against the Plasmodium falciparum Dihydrofolate Reductase; A Comparative Study

Background: Malaria is a life-threatening disease caused by parasites that are transmitted to people by mosquitoes. An estimated 700,000 people were killed by malaria in 2010 globally and approximately half the world's population are at risk of the disease. Malaria is preventable and curable. Malaria is caused by a microscopic parasite called Plasmodium. Four species of this parasite infect humans to cause malaria but Plasmodium falciparum is the most deadly. Plasmodium is transmitted between people by blood-eating mosquitoes. Pyrimethamine is an antiparasitic medicine that helps prevent parasites from growing and reproducing in the body. Materials and Methods: The C=O derivative of gedunin was designed using the ChemAxon software where the methyl group attachment of gedunin was substituted for the C=O group and converted into an mrv file. The mrv file was converted into SMILES strings for the purpose of docking using the Open Babel software. The AutoDock Vina software was utilized for the molecular docking process and the in-silico pharmacokinetics parameters of the C=O derivative of gedunin was predicted using the SwissADME server. Results: Results from the physiochemical characteristics prediction of the Plasmodium falciparum DHFR showed that the half life of the enzyme in human reticulocytes can be estimated at 30 hours when subjected to an in vitro study. The in silico pharmacokinetics study also showed that both the C=O derivative of gedunin and pyrimethamine violated none of the lipinski's rule. Results from the molecular docking study of the compounds (C=O derivative of gedunin and pyrimethamine) against the Plasmodium falciparum DHFR were -9.0 and -8.0Kcal/mol respectively. Conclusion: The above results showed that both experimental compounds can be safe for oral administration haven satisfied the lipinski's rule requirements. The molecular docking study also showed that the C=O derivative of gedunin might be a better antimalarial agent by its exhibition of a higher binding energy against the Plasmodium falciparum DHFR.