Identification of small molecule inhibitors of anthrax lethal factor.
Nat Struct Mol Biol
; 11(1): 67-72, 2004 Jan.
Article
em En
| MEDLINE
| ID: mdl-14718925
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Bacillus anthracis
/
Toxinas Bacterianas
/
Antígenos de Bactérias
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
Nat Struct Mol Biol
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos