A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease
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- 作者：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.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：May 3, 2007
- 年：2007
- 卷：50
- 期：9
- 页码：2127 - 2136
- 全文大小：515K
- 年卷期：v.50,no.9(May 3, 2007)
- ISSN：1520-4804
文摘
We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of thebotulinum 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 pHelevation 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 toidentify four new, potent inhibitors of this structural class (IC50's ranged from 3.2 to 17 
M). Moleculardocking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitorsthat we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs ofthe new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuableinformation about pharmacophore component contributions to inhibition.
M). Moleculardocking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitorsthat we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs ofthe new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuableinformation about pharmacophore component contributions to inhibition.