Comparative Analysis of Novel Targets for Antimalarial Drugs: Structural and Mechanistic Insights about Plasmodium falciparum Enzymes

Plasmodium falciparum, the causative agent of severe human malaria. The dominance of resistant strains has compelled to the discovery and development of new and different modes-ofaction. Current plasmodial drug discovery efforts remains lack far-reaching set of legitimated drug targets. Prerequisite of these targets (or the pathways in which they function) is that they prove to be crucial for parasite survival. Thioredoxin Reductase is a flavoprotein that catalyzes the NADPH-dependent reduction of thioredoxin. It plays an important role in maintaining the redox environment of the cell. A third redox active group transfers the reducing equivalent from the apolar active site to the surface of protein. This group is a second redox active disulfide in thioredoxin reductase. The vital importance of the thioredoxin redox cycle (encompassing NADPH, thioredoxin reductase and thioredoxin) is stressed by the confirmation that thioredoxin reductase is indispensable for the survival of intraerythrocytic P. falciparum. Cytosolic Plasmodium falciparum Spermidine synthase linked with the polyamine metabolism is a potential target for antimalarial chemotherapy due to the vital role of spermidine in the activation of the eukaryotic translation initiation factor 5A, cell proliferation and the mechanism of the aminopropyltransferase action of Spermidine Synthase. Methyl Erythritol 4-Phosphate (MEP)/Rohmer pathway is assumed to have specific inhibitors designed against enzymes of this pathway with less toxicity and fewer side effects. 2C-Methyl-dErythritol 2, 4 – Cyclodiphosphate Synthase (MECPS), catalyzes the formation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate. All three enzymes represents as promising drug targets for rational drug designing.