Identification of small molecule inhibitors of anthrax lethal factor Academic Article uri icon


MeSH Major

  • Antigens, Bacterial
  • Bacillus anthracis
  • Bacterial Toxins


  • The virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have K(i) values in the 0.5-5 microM range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF.

publication date

  • January 2004



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1038/nsmb711

PubMed ID

  • 14718925

Additional Document Info

start page

  • 67

end page

  • 72


  • 11


  • 1