title: Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype A inhibitors in a three-zone pharmacophore.
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.
authors.affiliation: Target Structure-Based Drug Discovery Group, SAIC-Frederick, Inc. National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, USA.
authors.forename: Ann R
authors.initials: AR
authors.lastname: Hermone
authors.forename: James C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Nuss
authors.forename: Lyal E
authors.initials: LE
authors.lastname: Tressler
authors.forename: Tam L
authors.initials: TL
authors.lastname: Nguyen
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Solaja
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: James J
authors.initials: JJ
authors.lastname: Schmidt
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
mesh_terms: D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002911:Chrysenes / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D021621:Imaging, Three-Dimensional; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D002911:Chrysenes; D019274:Botulinum Toxins, Type A