Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening

Igor A. Schepetkin, Andrey Ivanovich Khlebnikov, Liliya N. Kirpotina, Mark T. Quinn

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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 μM, 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.

Original languageEnglish
Pages (from-to)5232-5244
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number17
Publication statusPublished - 24 Aug 2006
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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