Abstract:
Dihydrofolate reductase (DHFR) is an enzyme catalyses NADPH dependent reduction of the 5,6-double bond of dihydrofolate to tetrahydrofolate in malaria parasite. The specificity, i.e., the synthesis of pyrimidine in plasmodium by de novo pathway, which does not occur in human, makes the enzyme a valuable target for the therapeutic agents. Antifolate antimalarial drugs interfere with folate metabolism, a pathway essential to malaria parasite survival and can develop resistance to many class of drugs, which is associated with mutations in the active site. Resistance to DHFR inhibitory antimalarial drugs (pyrimethamine and cycloguanil) is found to be associated with point mutations in the parasite DHFR gene sequence. A mutation of 108th residue leads to pyrimethamine resistance whereas resistance to cycloguanil occurs due to mutation at 16th residue. The resistance of the parasite against the single as well as the combination therapy has led to search new effective inhibitors for combating the resistant parasites. Insights from the knowledge of active site of DHFR structure suggest certain requirements for the design of new inhibitors. The structure of the active site of enzyme DHFR reveals that binding the inhibitors to the enzyme, the molecule must contain a heterocyclic like nucleus with groups capable of hydrogen bonding and non-polar group to fit into the hydrophobic core of the active site.
Richa Mishra, Brijeshkunvar Mishra and N.S. Hari Narayana Moorthy , 2006. Dihydrofolate Reductase Enzyme: A Potent Target for Antimalarial Research. Asian Journal of Cell Biology, 1: 48-58.
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