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 journalArticle

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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 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
Volume14
Issue number2
DOIs
StatePublished - Jan 15 2006

Fingerprint

Endopeptidases
Neurotoxins
Protease Inhibitors
Zinc
Molecules
Catalytic Domain
Antidotes
Poisons
Molecular Dynamics Simulation
Molecular dynamics
Serogroup
Screening
Throughput
Ions
Ligands
Atoms
Computer simulation
Enzymes
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

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

Cite this

Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A. / Park, Jewn Giew; Sill, Peter C.; Makiyi, Edward F.; Garcia-Sosa, Alfonso T.; Millard, Charles B.; Schmidt, James J.; Pang, Yuan-Ping.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 2, 15.01.2006, p. 395-408.

Research output: Contribution to journalArticle

Park, Jewn Giew ; Sill, Peter C. ; Makiyi, Edward F. ; Garcia-Sosa, Alfonso T. ; Millard, Charles B. ; Schmidt, James J. ; Pang, Yuan-Ping. / Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A. In: Bioorganic and Medicinal Chemistry. 2006 ; Vol. 14, No. 2. pp. 395-408.
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