Publication

Abstract : Antimalarial antifolates have been the central drugs for prophylaxis and treatment of malaria. Plasmodium falciparum readily develops resistance to the antifolates pyrimethamine and proguanil through a particular set of mutations in the dihydrofolate reductase (DHFR) gene that results in the less competitive drug binding at the site of the enzyme. Similar mutations can be found in the DHFR gene in Plasmodium vivax (DHFR) also. The aim of this research work is to reveal the interactions of the DHFR inhibitors with the target proteins and to investigate the effect of mutations computationally. Commonly used antifolate drugs against malaria such as trimethoprim, pyrimethamine, proguanil and WR99210 have been considered for the analysis. Proteins which are targeted by the antifolate drugs in malarial organisms have been identified and characterized. Interaction studies of the wild and mutated DHFR proteins with the known drugs have been made. It has been found that the ligand binding to mutated proteins is considerably low compared to that of the wild proteins in most of the cases except WR99210 drug. This discloses the inadequacy of the antifolate drugs and the need to improve the antimalarial antifolate in vivo effectiveness and to recognize powerful novel antifolate agents. From the interaction studies of antifolate drugs against the target DHFR in malarial parasites Plasmodium vivax and Plasmodium falciparum it has been identified that these parasites show resistance to the chemotherapeutic antifolate drugs. A combination of antifolate drugs can be effective against malarial parasites or a designing of a new antifolate drug. © 2011 IEEE.