Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model. Issue 18 (15th September 2016)

• Record Type: Journal Article
• Authors: Kumar, Gyanendra; Agarwal, Rakhi; Swaminathan, Subramanyam
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 18(2016)
• Page Start: 3978
• Page End: 3985
• Publication Date: 2016-09-15
• Subjects: Botulinum neurotoxin -- Fluorene -- Inhibitor -- Structure–activity relationship -- Pharmacophore; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.06.036
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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. 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.