eprintid: 19221
rev_number: 16
userid: 1419
dir: disk0/00/01/92/21
datestamp: 2013-07-03 14:55:56
lastmod: 2019-02-05 12:55:05
status_changed: 2013-07-03 14:55:56
type: article
metadata_visibility: show
item_issues_count: 0
eprint_status: archive
creators_name: Hermone, AR
creators_name: Burnett, JC
creators_name: Nuss, JE
creators_name: Tressler, LE
creators_name: Nguyen, TL
creators_name: Šolaja, BA
creators_name: Vennerstrom, JL
creators_name: Schmidt, JJ
creators_name: Wipf, P
creators_name: Bavari, S
creators_name: Gussio, R
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creators_email: pwipf@pitt.edu
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creators_id: PWIPF
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title: Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype a inhibitors in a three-zone pharmacophore
ispublished: pub
divisions: sch_as_chemistry
full_text_status: public
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.
date: 2008-12-15
date_type: published
publication: ChemMedChem
volume: 3
number: 12
pagerange: 1905 - 1912
refereed: TRUE
issn: 1860-7179
id_number: 10.1002/cmdc.200800241
pmid: 19006141
mesh_headings: Botulinum Toxins, Type A--antagonists & inhibitors
mesh_headings: Botulinum Toxins, Type A--pharmacology
mesh_headings: Chrysenes--chemistry
mesh_headings: Chrysenes--pharmacology
mesh_headings: Computer Simulation
mesh_headings: Databases, Factual
mesh_headings: Drug Design
mesh_headings: Imaging, Three-Dimensional
mesh_headings: Models, Molecular
mesh_headings: Structure-Activity Relationship
chemical_names: Chrysenes
chemical_names: Botulinum Toxins, Type A
citation:   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     
document_url: http://d-scholarship-dev.library.pitt.edu/19221/1/licence.txt