Accession Number:

ADA443596

Title:

Serotype-Selective, Small-Molecule Inhibitors of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

Descriptive Note:

Corporate Author:

ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD

Report Date:

2006-01-01

Pagination or Media Count:

15.0

Abstract:

Botulinum neurotoxin serotype A BoNTA is one of the most toxic substances known. Currently there is no antidote to BoNTA. Small molecules identified from high-throughput screening reportedly inhibit the endopeptidase - the zinc-bound, catalytic domain of BoNTA - at a drug concentration of 20 M. However, optimization of these inhibitors is hampered by challenges including the computational evaluation of the ability of a zinc ligand to compete for coordination with nearby residues in the active site of BoNTA. No improved inhibitor of the endopeptidase has been reported. This article reports the development of a serotype-specific small-molecule inhibitor of BoNTA with Ki of 12 m. it suggests that multiple molecular dynamics simulations using the cationic dummy atom approach are useful to structure-based design of zinc protease inhibitors.

Subject Categories:

  • Toxicology
  • Microbiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE