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

  1. Author:
    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.
    Solaja, B. A.
    Bavari, S.

  2. Author Address

    Univ Belgrade, Fac Chem, Belgrade 11001, Serbia. SAIC Frederick Inc, Target Struct Based Discovery Grp, Natl Canc Inst, Frederick, MD 21702 USA. Inst Chem Technol & Met, Belgrade 11001, Serbia. Univ Nebraska, Med Ctr, Coll Pharm, Omaha, NE 68198 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. NCI Frederick, Dev Therapeut Program, Ft Detrick, MD 21702 USA.;Solaja, BA, Univ Belgrade, Fac Chem, Studentski Trg 16,POB 158, Belgrade 11001, Serbia.;bsolaja@chem.bg.ac.yu sina.bavari@us.army.mil
    1. Year: 2007
    2. Date: May
  2. Journal: Journal of Medicinal Chemistry
    1. 50
    2. 9
    3. Pages: 2127-2136
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. 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 mu M). 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.

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External Sources

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  2. DOI: 10.1021/jm061446e
  3. View record in Web of Science®
  4. WOS: 000245954600015

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