PfDHFR Enzyme Inhibitors: Rational Design Using Pharmacoinformatic Tools
Pp. 228-273 (46)
Sheenu Abbat, Shweta Bhagat and Prasad V. Bharatam
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.
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.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S Nagar-160 062, Punjab, India.