title: In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors.
abstract: The need for novel therapeutics against Plasmodium falciparum is urgent due to recent emergence of multi-drug resistant malaria parasites. Since fatty acids are essential for both the liver and blood stages of the malarial parasite, targeting fatty acid biosynthesis is a promising strategy for combatting P. falciparum. We present a combined computational and experimental study to identify novel inhibitors of enoyl-acyl carrier protein reductase (PfENR) in the fatty acid biosynthesis pathway. A small-molecule database from ChemBridge was docked into three distinct PfENR crystal structures that provide multiple receptor conformations. Two different docking algorithms were used to generate a consensus score in order to rank possible small molecule hits. Our studies led to the identification of five low-micromolar pyrimidine dione inhibitors of PfENR.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA, slindert@ucsd.edu.
authors.forename: Steffen
authors.initials: S
authors.lastname: Lindert
authors.forename: Lorillee
authors.initials: L
authors.lastname: Tallorin
authors.forename: Quynh G
authors.initials: QG
authors.lastname: Nguyen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Burkart
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D019540:Area Under Curve; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation / Q000379:methods; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)