The rod-shaped, spore-forming bacterium Bacillus anthracis has emerged as one of the most dangerous biological weapons. The lethal factor (LF) enzyme, a zinc metalloprotein, is the primary agent of anthrax-related toxicity. Although LF is an attractive target for rational drug design, relatively few published inhibitors have demonstrated activity in cell-based assays and no LF inhibitor is currently available as a preventive or therapeutic agent. This study presents a new pharmacophore model designed to rapidly identify and prioritize promising LF inhibitor scaffolds from virtual compound libraries. The eight-featured, comprehensive pharmacophore model was obtained from experimental X-ray binding modes of structurally diverse active compounds and spanning all three key subsites in the LF binding area. All eight features of the model were validated to be essential in identifying active compounds and rejecting inactives by our significance test. When applied with a partial match criterion of at least five features, our pharmacophore model successfully identified 72.1% of the LF inhibitors in an unbiased test set of 68 nanomolar-level LF inhibitors that are not structurally related to the compounds used in pharmacophore construction, and returned none of the published compounds with specified activities greater than 100 �M. Key design principles for active LF inhibitors are also illustrated by this pharmacophore model.

??Novel, comprehensive, and validated pharmacophore model for anthrax toxin lethal factor inhibitors

246th National Meeting (2013)

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