Hermone, AR and Burnett, JC and Nuss, JE and Tressler, LE and Nguyen, TL and Šolaja, BA and Vennerstrom, JL and Schmidt, JJ and Wipf, P and Bavari, S and 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.
ISSN 1860-7179
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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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.
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Details
Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
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Hermone, AR | | | | Burnett, JC | | | | Nuss, JE | | | | Tressler, LE | | | | Nguyen, TL | | | | Šolaja, BA | | | | Vennerstrom, JL | | | | Schmidt, JJ | | | | Wipf, P | pwipf@pitt.edu | PWIPF | | Bavari, S | | | | Gussio, R | | | |
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Date: |
15 December 2008 |
Date Type: |
Publication |
Journal or Publication Title: |
ChemMedChem |
Volume: |
3 |
Number: |
12 |
Page Range: |
1905 - 1912 |
DOI or Unique Handle: |
10.1002/cmdc.200800241 |
Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
Refereed: |
Yes |
ISSN: |
1860-7179 |
MeSH Headings: |
Botulinum Toxins, Type A--antagonists & inhibitors; Botulinum Toxins, Type A--pharmacology; Chrysenes--chemistry; Chrysenes--pharmacology; Computer Simulation; Databases, Factual; Drug Design; Imaging, Three-Dimensional; Models, Molecular; Structure-Activity Relationship |
PubMed ID: |
19006141 |
Date Deposited: |
03 Jul 2013 14:55 |
Last Modified: |
05 Feb 2019 12:55 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/19221 |
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