Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity |
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Authors: | Burnett James C Schmidt James J Stafford Robert G Panchal Rekha G Nguyen Tam L Hermone Ann R Vennerstrom Jonathan L McGrath Connor F Lane Douglas J Sausville Edward A Zaharevitz Daniel W Gussio Rick Bavari Sina |
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Affiliation: | Developmental Therapeutics Program, NCI Frederick, Frederick, MD 21702, USA. |
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Abstract: | Botulinum neurotoxins (BoNTs) are among the most lethal biological substances to have been weaponized and are listed as biodefense category A agents. Currently, no small molecule (non-peptidic) therapeutics exist to counter this threat; hence, identifying and developing compounds that inhibit BoNTs is a high priority. In the present study, a high-throughput assay was used to identify small molecules that inhibit the metalloprotease activity of BoNT serotype A light chain (BoNT/A LC). All inhibitors were further verified using a HPLC-based assay. Conformational analyses of these compounds, in conjunction with molecular docking studies, were used to predict structural features that contribute to inhibitor binding and potency. Based on these results, a common pharmacophore for BoNT/A LC inhibitors is proposed. This is the first study to report small molecules (non-peptidics) that inhibit BoNT/A LC metalloprotease activity in the low microM range. |
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Keywords: | Bioterrorism Botulinum neurotoxin Drug discovery High-throughput screen Inhibitors Molecular modeling Pharmacophore Three-dimensional database search Metalloprotease |
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