A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease.
We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dual-function BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC50's ranged from 3.2 to 17 muM). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition.
Burnett
James C
JC
SAIC-Frederick, Inc., Target Structure-Based Drug Discovery Group, Frederick, Frederick, Inc., National Cancer Institute at Frederick, P.O. Box B, F.V.C. 310, Frederick, Maryland 21702, USA.
Opsenica
Dejan
D
Sriraghavan
Kamaraj
K
Panchal
Rekha G
RG
Ruthel
Gordon
G
Hermone
Ann R
AR
Nguyen
Tam L
TL
Kenny
Tara A
TA
Lane
Douglas J
DJ
McGrath
Connor F
CF
Schmidt
James J
JJ
Vennerstrom
Jonathan L
JL
Gussio
Rick
R
Solaja
Bogdan A
BA
Bavari
Sina
S
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D045726:Metalloproteases; D019274:Botulinum Toxins, Type A