Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening

Igor A. Schepetkin,^† Andrei I. Khlebnikov,^‡ Liliya N. Kirpotina,^† and Mark T. Quinn*^†

J. Med. Chem., 2006, 49 (17), pp 5232–5244

DOI: 10.1021/jm0605132

Publication Date (Web): July 28, 2006

 

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 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.