Serotype-Selective, Small-Molecule Inhibitors of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A
ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
Pagination or Media Count:
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.