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 μM range.
Original language | English (US) |
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Pages (from-to) | 84-93 |
Number of pages | 10 |
Journal | Biochemical and Biophysical Research Communications |
Volume | 310 |
Issue number | 1 |
DOIs | |
State | Published - Oct 10 2003 |
Keywords
- Bioterrorism
- Botulinum neurotoxin
- Drug discovery
- High-throughput screen
- Inhibitors
- Metalloprotease
- Molecular modeling
- Pharmacophore
- Three-dimensional database search
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Molecular Biology
- Cell Biology