In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors
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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.
KeywordsComputer-aided drug discovery Enoyl-acyl carrier protein reductase Virtual screening
We would like to thank Dr. Jacob Durrant for helpful discussions and careful reading of the manuscript. Additionally we would like to thank Dr. Victoria Feher for her help with ordering the ChemBridge compounds. This work was supported by the National Institutes of Health NIH R21A090213, NIH R01GM094924, and NIH R01GM095970 (MDB), and the National Science Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the National Biomedical Computation Resource, and the NSF Supercomputer Centers (JAM). Computational resources were supported, in part, by the National Science Foundation grant PHY-0822283, the Center for Theoretical Biological Physics. S. L. was supported by the American Heart Association (12POST11570005) and the Center for Theoretical Biological Physics. L.T. was supported by the San Diego Match Fellowship and the University of California Interfaces Training Grant. We would like to acknowledge the UCSD Chemistry and Biochemistry Mass Spectrometry Facility; Professor Pieter Dorrestein and Dr. Jane Yang for providing the P. falciparum ENR plasmid; Dr. James La Clair, Dr. Joris Beld, and Christopher Vickery for manuscript design and input; and Dr. Nicolas Kosa for enzymatic assay and protein expression consulting.
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