title: A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease.
abstract: 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.
authors.affiliation: 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.
authors.forename: James C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Dejan
authors.initials: D
authors.lastname: Opsenica
authors.forename: Kamaraj
authors.initials: K
authors.lastname: Sriraghavan
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.forename: Ann R
authors.initials: AR
authors.lastname: Hermone
authors.forename: Tam L
authors.initials: TL
authors.lastname: Nguyen
authors.forename: Tara A
authors.initials: TA
authors.lastname: Kenny
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Lane
authors.forename: Connor F
authors.initials: CF
authors.lastname: McGrath
authors.forename: James J
authors.initials: JJ
authors.lastname: Schmidt
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Solaja
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: 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
chemical_list: D000634:Aminoquinolines; D045726:Metalloproteases; D019274:Botulinum Toxins, Type A