Serotype-Selective, Small-Molecule Inhibitors of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2006
- Accession Number
- ADA443596
Entities
People
- Alfonso T. Garcia-sosa
- Charles B. Millard
- Edward F. Makiyi
- James J. Schmidt
- Jewn G. Park
- Peter C. Sill
- Yuan-Ping Pang
Organizations
- United States Army Medical Research Institute of Infectious Diseases