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Title: Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model

Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. In addition, the structure–activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC 50 values.
Authors:
ORCiD logo [1] ;  [1] ;  [1]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States). Biology Department
Publication Date:
Report Number(s):
BNL-112325-2016-JA
Journal ID: ISSN 0968-0896
Grant/Contract Number:
SC0012704; AC02-98CH10886; DEAC02-98CH10886
Type:
Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry
Additional Journal Information:
Journal Volume: 24; Journal Issue: 18; Journal ID: ISSN 0968-0896
Publisher:
Elsevier
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Botulinum neurotoxin; fluorene; inhibitor; structure-activity relationship; pharmacophore
OSTI Identifier:
1336050
Alternate Identifier(s):
OSTI ID: 1398009

Kumar, Gyanendra, Agarwal, Rakhi, and Swaminathan, Subramanyam. Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model. United States: N. p., Web. doi:10.1016/j.bmc.2016.06.036.
Kumar, Gyanendra, Agarwal, Rakhi, & Swaminathan, Subramanyam. Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model. United States. doi:10.1016/j.bmc.2016.06.036.
Kumar, Gyanendra, Agarwal, Rakhi, and Swaminathan, Subramanyam. 2016. "Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model". United States. doi:10.1016/j.bmc.2016.06.036. https://www.osti.gov/servlets/purl/1336050.
@article{osti_1336050,
title = {Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model},
author = {Kumar, Gyanendra and Agarwal, Rakhi and Swaminathan, Subramanyam},
abstractNote = {Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. In addition, the structure–activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC50 values.},
doi = {10.1016/j.bmc.2016.06.036},
journal = {Bioorganic and Medicinal Chemistry},
number = 18,
volume = 24,
place = {United States},
year = {2016},
month = {6}
}