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  • Title: Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening.
    Author: Schepetkin IA, Khlebnikov AI, Kirpotina LN, Quinn MT.
    Journal: J Med Chem; 2006 Aug 24; 49(17):5232-44. PubMed ID: 16913712.
    Abstract:
    Anthrax lethal factor (LF) is a key virulence factor of anthrax lethal toxin. We screened a chemolibrary of 10,000 drug-like molecules for their ability to inhibit LF and identified 18 novel small molecules with potent LF inhibitory activity. Three additional LF inhibitors were identified through further structure-activity relationship (SAR) analysis. All 21 compounds inhibited LF with an IC50 range of 0.8 to 11 muM, utilizing mixed-mode competitive inhibition. An evaluation of inhibitory activity against a range of unrelated proteases showed relatively high specificity for LF. Furthermore, pharmacophore modeling of these compounds showed a high degree of similarity to the model published by Panchal et al. (Nat. Struct. Mol. Biol. 2004, 11, 67-72), indicating that the conformational features of these inhibitors are structurally compatible with the steric constraints of the substrate-binding pocket. These novel LF inhibitors and the structural scaffolds identified as important for inhibitory activity represent promising leads to pursue for further LF inhibitor development.
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