Development of specific DHODH inhibitors for Plasmodium and Human species

Abstract

Malaria still remains one of the challenging public health issue infecting about 300-500 millions of people. The most serious and fatal malarial infections are caused by Plasmodium falciparum which has developed resistance to commonly employed therapeutics. Hence the need to develop a novel anti-malarial drug targeting Dihydroorotate dehydrogenase (DHODH), an enzyme involved in parasite growth. DHODH is present in both humans and Plasmodium falciparum. Sequence analysis and structure comparison of DHODH of both Human and Plasmodium falciparum reveals variations among them, thereby providing a chance to design a specific inhibitor. Virtual screening of existing anti-malarial drugs acting on DHODH is performed from Pubchem and BindingDB databases. Pharmacophore mapping was done for the top 20 virtual screening compounds using hip hop algorithm. The compounds thus obtained from screening, are docked with both Human and Plasmodium DHODH. Potential anti-malarial lead compounds can be developed to treat resistant strains of Plasmodium falciparum.