A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

• Published in: Journal of medicinal chemistry 2007-05, Vol.50 (9), p.2127-2136
• Main Authors: Burnett, James C, Opsenica, Dejan, Sriraghavan, Kamaraj, Panchal, Rekha G, Ruthel, Gordon, Hermone, Ann R, Nguyen, Tam L, Kenny, Tara A, Lane, Douglas J, McGrath, Connor F, Schmidt, James J, Vennerstrom, Jonathan L, Gussio, Rick, Šolaja, Bogdan A, Bavari, Sina
• Format: Article
• Language: English
• Subjects: Aminoquinolines - chemical synthesis; Aminoquinolines - chemistry; Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; Botulinum Toxins, Type A - antagonists & inhibitors; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrolases; Medical sciences; Metalloproteases - antagonists & inhibitors; Metalloproteases - chemistry; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061446e

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 μM). 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.