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

Bioorg Med Chem. 2016 Sep 15;24(18):3978-3985. doi: 10.1016/j.bmc.2016.06.036. Epub 2016 Jun 18.

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.

Keywords: Botulinum neurotoxin; Fluorene; Inhibitor; Pharmacophore; Structure–activity relationship.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Botulinum Toxins / antagonists & inhibitors*
  • Botulinum Toxins / metabolism
  • Botulism / drug therapy
  • Botulism / metabolism
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Clostridium botulinum / drug effects*
  • Clostridium botulinum / metabolism
  • Fluorenes / chemistry*
  • Fluorenes / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology
  • Structure-Activity Relationship
  • Synaptosomal-Associated Protein 25 / chemistry
  • Synaptosomal-Associated Protein 25 / pharmacology

Substances

  • Anti-Bacterial Agents
  • Chelating Agents
  • Fluorenes
  • Peptidomimetics
  • Synaptosomal-Associated Protein 25
  • Botulinum Toxins
  • botulinum toxin type E