Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening.

ABSTRACT: Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent PfDHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known PfDHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25% inhibition of PfDHODH at a concentration of 10 ?M, three of which exhibited IC50 values in the range of 0.38-20 ?M. The most active compound, NSC336047, displayed species-selectivity for PfDHODH over human DHODH and inhibited parasite growth with an IC50 of 26 ?M. In addition to this, 13 compounds inhibited parasite growth with IC50 values of ? 50 ?M, 4 of which showed IC50 values in the range of 5-12 ?M. These compounds could be further explored in the identification and development of more potent PfDHODH and parasite growth inhibitors.

SUBMITTER: Pavadai E 

PROVIDER: S-EPMC4871132 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature