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

  1. Author:
    Park, J. G.
    Sill, P. C.
    Makiyi, E. F.
    Garcia-Sosa, A. T.
    Millard, C. B.
    Schmidt, J. J.
    Pang, Y. P.

  2. Author Address

    USA, Med Res Inst Infect Dis, Dept Cell Biol & Biochem, Toxicol & Aerobiol Div, Frederick, MD 21702 USA. Mayo Clin, Coll Med, Comp Aided Mol Design Lab, Rochester, MN 55905 USA. Walter Reed Army Inst Res, Div Biochem, Silver Spring, MD 20910 USA.;Schmidt, JJ, USA, Med Res Inst Infect Dis, Dept Cell Biol & Biochem, Toxicol & Aerobiol Div, 1425 Porter St, Frederick, MD 21702 USA.;james.schmidt@det.amedd.army.mil pang@mayo.edu
    1. Year: 2006
    2. Date: Jan
  2. Journal: Bioorganic & Medicinal Chemistry
    1. 14
    2. 2
    3. Pages: 395-408
  4. Type of Article: Article
  5. ISSN: 0968-0896
  1. 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 mu 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-selective, small-molecule inhibitor of BoNTA with a K-i of 12 mu M. 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. (c) 2005 Elsevier Ltd. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.bmc.2005.08.018
  3. View record in Web of Science®
  4. WOS: 000234091500010

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