title: 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 μM, three of which exhibited IC50 values in the range of 0.38-20 μM. The most active compound, NSC336047, displayed species-selectivity for PfDHODH over human DHODH and inhibited parasite growth with an IC50 of 26 μM. In addition to this, 13 compounds inhibited parasite growth with IC50 values of ≤ 50 μM, 4 of which showed IC50 values in the range of 5-12 μM. These compounds could be further explored in the identification and development of more potent PfDHODH and parasite growth inhibitors.
authors.forename: Elumalai
authors.initials: E
authors.lastname: Pavadai
authors.affiliation: Departments of Pharmacology, University of Texas Southwestern Medical Center at Dallas , 6001 Forest Park Blvd, Dallas, Texas 75390-9041, United States.
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , 4002 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.affiliation: Departments of Pharmacology, University of Texas Southwestern Medical Center at Dallas , 6001 Forest Park Blvd, Dallas, Texas 75390-9041, United States.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000818:Animals; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors