Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype A inhibitors in a three-zone pharmacophore.
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.
Hermone
Ann R
AR
Target Structure-Based Drug Discovery Group, SAIC-Frederick, Inc. National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, USA.
Burnett
James C
JC
Nuss
Jonathan E
JE
Tressler
Lyal E
LE
Nguyen
Tam L
TL
Solaja
Bogdan A
BA
Vennerstrom
Jonathan L
JL
Schmidt
James J
JJ
Wipf
Peter
P
Bavari
Sina
S
Gussio
Rick
R
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
D002911:Chrysenes; D019274:Botulinum Toxins, Type A