| Autor: |
Burnett JC; SAIC-Frederick, Inc., Target Structure-Based Drug Discovery Group, Frederick, Frederick, Inc., National Cancer Institute at Frederick, P.O. Box B, F.V.C. 310, Frederick, Maryland 21702, USA., Opsenica D, Sriraghavan K, Panchal RG, Ruthel G, Hermone AR, Nguyen TL, Kenny TA, Lane DJ, McGrath CF, Schmidt JJ, Vennerstrom JL, Gussio R, Solaja BA, Bavari S |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2007 May 03; Vol. 50 (9), pp. 2127-36. Date of Electronic Publication: 2007 Apr 07. |
| DOI: |
10.1021/jm061446e |
| Abstrakt: |
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 muM). 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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