title: Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure-activity relationship and a pharmacophore model.
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.
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Rakhi
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA. Electronic address: swami@bnl.gov.
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001906:Botulism / Q000188:drug therapy / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D003014:Clostridium botulinum / Q000187:drug effects* / Q000378:metabolism; D005449:Fluorenes / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D005449:Fluorenes; D057786:Peptidomimetics; D050825:Synaptosomal-Associated Protein 25; D001905:Botulinum Toxins; C096326:botulinum toxin type E
keywords: Botulinum neurotoxin; Fluorene; Inhibitor; Pharmacophore; Structure–activity relationship