Identification of Slow-Binding Inhibitors of the BoNT/A Protease.
Ealin N PatelLewis D TurnerMark S HixonKim D JandaPublished in: ACS medicinal chemistry letters (2022)
Botulinum neurotoxin A (BoNT/A) is a lethal toxin, which causes botulism, and is categorized as a bioterrorism threat, which causes flaccid paralysis and death. Botulinum A neurotoxicity is governed through its light chain (LC), a zinc metalloprotease. Pharmacological investigations aimed at negating BoNT/A's LC have typically looked to inhibitors that have been shown to inhibit the light chain's activity by reversible zinc chelation within its active site. This report outlines the first examples of nonpeptidic inhibitors of the BoNT/A LC that possess slow-binding kinetics, a needed logic to counteract the longevity of BoNT/A. Cyclopropane, alkyl, and alkenyl derivatives of 2,4-dichlorocinamic hydroxamic acid (DCHA) were shown to possess both one-step and two-step slow-binding kinetics. Structure-kinetic relationships (SKRs) were observed and were rationalized with the aid of docking models that predicted improved interactions with residues within a hydrophobic cleft adjacent to the active site.
Keyphrases
- simultaneous determination
- ionic liquid
- dna binding
- escherichia coli
- mass spectrometry
- binding protein
- liquid chromatography
- aqueous solution
- molecular dynamics simulations
- oxide nanoparticles
- small molecule
- protein protein
- tandem mass spectrometry
- high resolution
- high resolution mass spectrometry
- bioinformatics analysis