Journal of Computer-Aided Molecular Design

, Volume 29, Issue 1, pp 79–87 | Cite as

In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors

  • Steffen LindertEmail author
  • Lorillee Tallorin
  • Quynh G. Nguyen
  • Michael D. Burkart
  • J. Andrew McCammon


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.


Computer-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.

Supplementary material

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Supplementary material 1 (DOCX 2057 kb)


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Steffen Lindert
    • 1
    • 2
    • 3
    Email author
  • Lorillee Tallorin
    • 3
  • Quynh G. Nguyen
    • 3
  • Michael D. Burkart
    • 3
  • J. Andrew McCammon
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Department of PharmacologyUniversity of California San DiegoLa JollaUSA
  2. 2.Center for Theoretical Biological PhysicsLa JollaUSA
  3. 3.Department of Chemistry and BiochemistryUniversity of California San DiegoLa JollaUSA
  4. 4.Howard Hughes Medical InstituteUniversity of California San DiegoLa JollaUSA
  5. 5.National Biomedical Computation ResourceUniversity of California San DiegoLa JollaUSA

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