%0 Journal Article
%@ 1860-7179
%A Hermone, AR
%A Burnett, JC
%A Nuss, JE
%A Tressler, LE
%A Nguyen, TL
%A Šolaja, BA
%A Vennerstrom, JL
%A Schmidt, JJ
%A Wipf, P
%A Bavari, S
%A Gussio, R
%D 2008
%F pittir:19221
%J ChemMedChem
%N 12
%P 1905 - 1912
%T Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype a inhibitors in a three-zone pharmacophore
%U http://d-scholarship-dev.library.pitt.edu/19221/
%V 3
%X 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.