PfDHFR Enzyme Inhibitors: Rational Design Using Pharmacoinformatic Tools

Malaria is recognized as the most dangerous disease originating from parasites. Plasmodium falciparum dihydrofolate reductase (PfDHFR) is one of the important targets for anti-malarial drug design. All the reported anti-folates show drug resistance. Mutations in the active-site of PfDHFR enzyme, particularly at 16, 51, 59, 108, and 164 residues, are responsible for the observed resistance. The new strategies for anti-malarial drug discovery include design of leads which are effective against both wild type and mutant PfDHFR. Recent efforts in this direction lead to the identification of P218 as an important lead compound. In addition a set of guanylthiourea derivatives were also reported. Rational lead design strategies are being adopted for the design of PfDHFR inhibitors as anti-malarial agents. In this update, a review of the computeraided drug design which was adopted over the past decade, in the design of PfDHFR inhibitors, are elaborated. Efforts based on molecular docking, pharmacophore mapping, QSAR, homology modeling, and quantum chemical studies are discussed in detail. Special emphasis is given to the importance of drug action while discussing the pharmacoinformatic approaches. In future the rational methods of lead design and lead optimization are expected to increase because sufficient knowledge is already generated on the structural aspects of PfDHFR and its possible inhibitors are already available.

Keywords: Antifolates, anti-malarial, molecular docking, molecular dynamics, P. falciparum DHFR inhibitors, pharmacoinformatic tools and X-ray crystallographic analysis, pharmacophore mapping, QSAR, quadruple mutant enzyme, quantum medicinal chemistry, structure based drug design.