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Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype a inhibitors in a three-zone pharmacophore

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
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hermone, AR
Burnett, JC
Nuss, JE
Tressler, LE
Nguyen, TL
Šolaja, BA
Vennerstrom, JL
Schmidt, JJ
Wipf, Ppwipf@pitt.eduPWIPF
Bavari, S
Gussio, R
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.pitt.edu/id/eprint/19221

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