Modelling and informatics in the analysis of P-falciparum DHFR enzyme inhibitors

Malaria is one of the most prevalent diseases of our planet which claims millions of lives annually. Plasmodium falciparum is the causative agent of majority of the mortality and morbidity associated with malaria particularly in tropical countries. Resistance of the parasite to the currently available chemotherapeutic agents poses a serious threat to human being. Inhibition of P. falciparum dihydrofolate reductase (DHFR) enzyme has been used as one of the strategies in curbing malaria. However, due to mutation in the active-site of the enzyme particularly at 16, 51, 59, 108, and 164 residues, the parasite developed resistance to most of antifolate drugs such as cycloguanil and pyrimethamine. Thus, design of new and potent antimalarial agents which are effective against both wild-type and mutant enzymes is very essential in order to minimize burden of P. falciparum malaria. Computer-aided drug design approaches are playing a crucial role in the design of potential antimalarial drug candidates. In this article, molecular modelling studies based on docking, pharmacophore mapping, QSAR, homology modelling, and quantum chemical studies are reviewed. The importance of these methods in understanding mechanism of drug resistance at a molecular level, and design of antimalarial drug candidates are discussed briefly. The examples mentioned in the review could give insights into the wide range of possibilities of using computer-aided drug design (CADD) methodologies.