Plasmodium falciparum dihydroorotate dehydrogenase: a drug target against malaria

Abstract

Malaria remains one of the most lethal infectious diseases worldwide, and the most severe form is caused by Plasmodium falciparum. In recent decades, the major challenge to treatment of this disease has been the ability of the protozoan parasite to develop resistance to the drugs that are currently in use. Among P. falciparum enzymes, P. falciparum dihydroorotate dehydrogenase has been identified as an important target in drug discovery. Interference with the activity of this enzyme inhibits de novo pyrimidine biosynthesis and consequently prevents malarial infection. Organic synthesis, x-ray crystallography, high-throughput screening and molecular modeling methods such as molecular docking, quantitative structure–activity relationships, structure-based pharmacophore mapping and molecular dynamics simulations have been applied to the discovery of new inhibitors of P. falciparum dihydroorotate dehydrogenase.