Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A

Jewn Giew Park, Peter C. Sill, Edward F. Makiyi, Alfonso T. Garcia-Sosa, Charles B. Millard, James J. Schmidt, Yuan Ping Pang

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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 μM. 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-selective, small-molecule inhibitor of BoNTA with a Ki of 12 μM. This inhibitor was designed to coordinate the zinc ion embedded in the active site of the enzyme for affinity and to interact with a species-specific residue in the active site for selectivity. It is the most potent small-molecule inhibitor of BoNTA reported to date. The results suggest that multiple molecular dynamics simulations using the cationic dummy atom approach are useful to structure-based design of zinc protease inhibitors.

Original languageEnglish (US)
Pages (from-to)395-408
Number of pages14
JournalBioorganic and Medicinal Chemistry
Issue number2
StatePublished - Jan 15 2006


  • Antidotes
  • Countermeasures
  • Protease
  • Structure-based drug design
  • Zinc protein simulations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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