Development of a comprehensive, validated pharmacophore hypothesis for anthrax toxin lethal factor (LF) inhibitors using genetic algorithms, Pareto scoring, and structural biology.

ABSTRACT: Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. The anthrax toxin lethal factor (LF), an 89-kDa zinc hydrolase secreted by the bacilli, is the toxin component chiefly responsible for pathogenesis and has been a popular target for rational and structure-based drug design. Although hundreds of small-molecule compounds have been designed to target the LF active site, relatively few reported inhibitors have exhibited activity in cell-based assays, and no LF inhibitor is currently available to treat or prevent anthrax. This study presents a new pharmacophore map assembly, validated by experiment, designed to rapidly identify and prioritize promising LF inhibitor scaffolds from virtual compound libraries. The new hypothesis incorporates structural

SUBMITTER: Chiu TL 

PROVIDER: S-EPMC3477282 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature