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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
Author(s) -
Hermone Ann R.,
Burnett James C.,
Nuss Jonathan E.,
Tressler Lyal E.,
Nguyen Tam L.,
Šolaja Bogdan A.,
Vennerstrom Jonathan L.,
Schmidt James J.,
Wipf Peter,
Bavari Sina,
Gussio Rick
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800241
Subject(s) - pharmacophore , steric effects , botulinum neurotoxin , chemistry , stereochemistry , combinatorial chemistry , docking (animal) , computational biology , virtual screening , small molecule , biochemistry , biology , medicine , toxin , nursing
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.