Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening
Identifieur interne : 004058 ( Main/Exploration ); précédent : 004057; suivant : 004059Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening
Auteurs : Igor A. Schepetkin [Russie] ; Andrei I. Khlebnikov [Russie] ; Liliya N. Kirpotina [Russie] ; Mark T. Quinn [Russie, États-Unis]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 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.
Url:
DOI: 10.1021/jm0605132
Affiliations:
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Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2006</date><date type="published">2006</date><biblScope unit="vol">49</biblScope><biblScope unit="issue">17</biblScope><biblScope unit="page" from="5232">5232</biblScope><biblScope unit="page" to="5244">5244</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="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.</div></front></TEI><affiliations><list><country><li>Russie</li><li>États-Unis</li></country></list><tree><country name="Russie"><noRegion><name sortKey="Schepetkin, Igor A" sort="Schepetkin, Igor A" uniqKey="Schepetkin I" first="Igor A." last="Schepetkin">Igor A. 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