In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors.
- Author(s): Lindert, Steffen;
- Tallorin, Lorillee;
- Nguyen, Quynh G;
- Burkart, Michael D;
- McCammon, J Andrew
- et al.
Published Web Locationhttp://dx.doi.org/10.1007/s10822-014-9806-3
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.