The anthrax toxin lethal factor (LF), an 89-kDa zinc metalloprotein secreted by the the bacterium Bacillus anthracis, is the toxin component chiefly responsible for anthrax pathogenesis and is a popular target for therapeutic design. Here we present novel and experimentally validated pharmacophore hypotheses that can rapidly identify and prioritize promising LF inhibitor scaffolds from virtual compound libraries.  These new models include structural information from all available LF enzyme-inhibitor complexes deposited in the Protein Data Bank (PDB) and include features from all three subsites of the LF binding area.  In extensive validation studies on over 500 compounds for which published LF biological activity data exist, our comprehensive model was strongly selective for compounds in the nanomolar range, successfully identifying 73.5% of nanomolar-level inhibitors while rejecting all weakly active (>100 mM) compounds.  In addition to its powerful capabilities as a database searching tool, the final, optimized model elucidates key LF ligand-receptor interactions found to influence compound potency.

Novel, comprehensive pharmacophore hypotheses for anthrax toxin lethal factor (LF) inhibitors

244th National Meeting (2012)

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