Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype a inhibitors in a three-zone pharmacophore

Ann R. Hermone, James C. Burnett, Jonathan E. Nuss, Lyal E. Tressler, Tam L. Nguyen, Bogdan A. Šolaja, Jonathan L. Vennerstrom, James J. Schmidt, Peter Wipf, Sina Bavari, Rick Gussio

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

A search query consisting of two aromatic centers and two cationic centers was defined based on previously identified small molecule inhibitors of the botulinum neurotoxin serotype A light chain (BoNT/A LC) and used to mine the National Cancer Institute Open Repository. Ten small molecule hits were identified, and upon testing, three demonstrated inhibitory activity. Of these, one was structurally unique, possessing a rigid diazachrysene scaffold. The steric limitations of the diazachrysene imposed a separation between the overlaps of previously identified inhibitors, revealing an extended binding mode. As a result, the pharmacophore for BoNT/A LC inhibition has been modified to encompass three zones. To demonstrate the utility of this model, a novel three-zone inhibitor was mined and its activity was confirmed.

Original languageEnglish (US)
Pages (from-to)1905-1912
Number of pages8
JournalChemMedChem
Volume3
Issue number12
DOIs
StatePublished - Dec 15 2008

Keywords

  • Biologically active compounds
  • Botulinum neurotoxin
  • Drug discovery
  • Molecular modeling
  • Screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Hermone, A. R., Burnett, J. C., Nuss, J. E., Tressler, L. E., Nguyen, T. L., Šolaja, B. A., Vennerstrom, J. L., Schmidt, J. J., Wipf, P., Bavari, S., & Gussio, R. (2008). Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype a inhibitors in a three-zone pharmacophore. ChemMedChem, 3(12), 1905-1912. https://doi.org/10.1002/cmdc.200800241