Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

James C. Burnett, James J. Schmidt, Robert G. Stafford, Rekha G. Panchal, Tam L. Nguyen, Ann R. Hermone, Jonathan L. Vennerstrom, Connor F. McGrath, Douglas J. Lane, Edward A. Sausville, Daniel W. Zaharevitz, Rick Gussio, Sina Bavari

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


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 languageEnglish (US)
Pages (from-to)84-93
Number of pages10
JournalBiochemical and Biophysical Research Communications
Issue number1
StatePublished - Oct 10 2003


  • 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


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