A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease

James C. Burnett, Dejan Opsenica, Kamaraj Sriraghavan, Rekha G. Panchal, Gordon Ruthel, Ann R. Hermone, Tam L. Nguyen, Tara A. Kenny, Douglas J. Lane, Connor F. McGrath, James J. Schmidt, Jonathan L. Vennerstrom, Rick Gussio, Bogdan A. Šolaja, Sina Bavari

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dual-function BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC50's ranged from 3.2 to 17 μM). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition.

Original languageEnglish (US)
Pages (from-to)2127-2136
Number of pages10
JournalJournal of Medicinal Chemistry
Volume50
Issue number9
DOIs
StatePublished - May 3 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Burnett, J. C., Opsenica, D., Sriraghavan, K., Panchal, R. G., Ruthel, G., Hermone, A. R., Nguyen, T. L., Kenny, T. A., Lane, D. J., McGrath, C. F., Schmidt, J. J., Vennerstrom, J. L., Gussio, R., Šolaja, B. A., & Bavari, S. (2007). A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease. Journal of Medicinal Chemistry, 50(9), 2127-2136. https://doi.org/10.1021/jm061446e