Celastrol inhibits Plasmodium falciparum enoyl-acyl carrier protein reductase

Bioorg Med Chem. 2014 Nov 1;22(21):6053-6061. doi: 10.1016/j.bmc.2014.09.002. Epub 2014 Sep 15.

Abstract

Enoyl-acyl carrier protein reductase (ENR), a critical enzyme in type II fatty acid biosynthesis, is a promising target for drug discovery against hepatocyte-stage Plasmodium falciparum. In order to identify PfENR-specific inhibitors, we docked 70 FDA-approved, bioactive, and/or natural product small molecules known to inhibit the growth of whole-cell blood-stage P. falciparum into several PfENR crystallographic structures. Subsequent in vitro activity assays identified a noncompetitive low-micromolar PfENR inhibitor, celastrol, from this set of compounds.

Keywords: Celastrol; Enoyl-acyl carrier protein reductase; Malaria; Plasmodium falciparum; in silico.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antimalarials / chemistry*
  • Antimalarials / pharmacology*
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / chemistry
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / metabolism
  • Humans
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / microbiology
  • Molecular Docking Simulation
  • Plasmodium falciparum / chemistry
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Triterpenes / chemistry*
  • Triterpenes / pharmacology*

Substances

  • Antimalarials
  • Triterpenes
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
  • celastrol