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-base...d derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition.
Source:
Journal of Medicinal Chemistry, 2007, 50, 9, 2127-2136
TY - JOUR
AU - Burnett, J.C.
AU - Opsenica, Dejan
AU - Sriraghavan, K.
AU - Panchal, R.G.
AU - Ruthel, G.
AU - Hermone, A.R.
AU - Nguyen, T.L.
AU - Kenny, T.A.
AU - Lane, D.J.
AU - McGrath, C.F.
AU - Schmidt, J.J.
AU - Vennerstrom, J.L.
AU - Gussio, R.
AU - Šolaja, Bogdan
AU - Bavari, S.
PY - 2007
UR - https://cer.ihtm.bg.ac.rs/handle/123456789/361
AB - 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.
PB - American Chemical Society (ACS)
T2 - Journal of Medicinal Chemistry
T1 - A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease
VL - 50
IS - 9
SP - 2127
EP - 2136
DO - 10.1021/jm061446e
ER -
@article{
author = "Burnett, J.C. and Opsenica, Dejan and Sriraghavan, K. and Panchal, R.G. and Ruthel, G. and Hermone, A.R. and Nguyen, T.L. and Kenny, T.A. and Lane, D.J. and McGrath, C.F. and Schmidt, J.J. and Vennerstrom, J.L. and Gussio, R. and Šolaja, Bogdan and Bavari, S.",
year = "2007",
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 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.",
publisher = "American Chemical Society (ACS)",
journal = "Journal of Medicinal Chemistry",
title = "A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease",
volume = "50",
number = "9",
pages = "2127-2136",
doi = "10.1021/jm061446e"
}
Burnett, J.C., Opsenica, D., Sriraghavan, K., Panchal, R.G., Ruthel, G., Hermone, A.R., Nguyen, T.L., Kenny, T.A., Lane, D.J., McGrath, C.F., Schmidt, J.J., Vennerstrom, J.L., Gussio, R., Šolaja, B.,& Bavari, S.. (2007). A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease. in Journal of Medicinal Chemistry
American Chemical Society (ACS)., 50(9), 2127-2136.
https://doi.org/10.1021/jm061446e
Burnett J, Opsenica D, Sriraghavan K, Panchal R, Ruthel G, Hermone A, Nguyen T, Kenny T, Lane D, McGrath C, Schmidt J, Vennerstrom J, Gussio R, Šolaja B, Bavari S. A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease. in Journal of Medicinal Chemistry. 2007;50(9):2127-2136.
doi:10.1021/jm061446e .
Burnett, J.C., Opsenica, Dejan, Sriraghavan, K., Panchal, R.G., Ruthel, G., Hermone, A.R., Nguyen, T.L., Kenny, T.A., Lane, D.J., McGrath, C.F., Schmidt, J.J., Vennerstrom, J.L., Gussio, R., Šolaja, Bogdan, Bavari, S., "A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease" in Journal of Medicinal Chemistry, 50, no. 9 (2007):2127-2136,
https://doi.org/10.1021/jm061446e . .
