Lead Hopping for PfDHODH Inhibitors as Antimalarials Based on Pharmacophore Mapping, Molecular Docking and Comparative Binding Energy Analysis (COMBINE): A Three-Layered Virtual Screening Approach

摘要

Malaria is a major worldwide public health threat securing the fifth position among the top ten causes of worldwide death with worrying social and economic burdens due to the rapid emergence of resistance to the currently available antimalarial drugs like chloroquine, sulfadoxine-pyrimetha-mine including Artemisinin.The causative agent for the disease is a parasite belonging to the Plasmodium species transmitted to human by the aid of female Anopheles mosquito. Although several antimalarial drugs have been reported till date, the efficacy of these drugs has been severely limited by widespread drug resistance necessitating new target based therapy. The enzymes governing the pyrimidine biosynthesis within the malarial parasite constitute essential targets for a number of clinically effective therapies since the pyrimidine metabolism pathway proves to be a vulnerable component of the parasite's biology. Amongst the chemically validated targets, P. falciparum di-hydroorotate dehydrogenase (PfDHODH), present in the mitochondria, is one of the essential druggable targets identified against P. falciparum that catalyses fourth reaction (formation of dihydroorotate to orotate which represents the rate limiting step in de novo pyrimidine biosynthesis) of pyrimidine de novo biosynthesis. Inhibition of the enzyme