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Inhibition of metalloprotease botulinum serotype A from a pseudo-peptide binding mode to a small molecule that is active in primary neurons

  1. Author:
    Burnett, J. C.
    Ruthel, G.
    Stegmann, C. M.
    Panchal, R. G.
    Nguyen, T. L.
    Hermone, A. R.
    Stafford, R. G.
    Lane, D. J.
    Kenny, T. A.
    McGrath, C. F.
    Wipf, P.
    Stahl, A. M.
    Schmidt, J. J.
    Gussio, R.
    Brunger, A. T.
    Bavari, S.
  2. Author Address

    Stanford Univ, Sch Med, HHMI, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Stanford Synchrotron Radiat Lab, Stanford, CA 94305 USA. NCI Frederick, Informat Technol Branch, Dev Therapeut Program, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. SAIC Frederick, Target Struct Based Drug Discovery Grp, Frederick, MD USA. Univ Pittsburgh, Combinatorial Chem Ctr, Pittsburgh, PA 15260 USA.;Brunger, AT, Stanford Univ, Sch Med, HHMI, 318 Campus Dr,Rm E300, Stanford, CA 94305 USA.;brunger@stanford.edu sina.bavari@us.army.mil
    1. Year: 2007
    2. Date: Feb
  1. Journal: Journal of Biological Chemistry
    1. 282
    2. 7
    3. Pages: 5004-5014
  2. Type of Article: Article
  3. ISSN: 0021-9258
  1. Abstract:

    An efficient research strategy integrating empirically guided, structure-based modeling and chemoinformatics was used to discover potent small molecule inhibitors of the botulinum neurotoxin serotype A light chain. First, a modeled binding mode for inhibitor 2-mercapto-3-phenylpropionyl-RATKML (K-i = 330 nM) was generated, and required the use of a molecular dynamic conformer of the enzyme displaying the reorientation of surface loops bordering the substrate binding cleft. These flexible loops are conformationally variable in x-ray crystal structures, and the model predicted that they were pivotal for providing complementary binding surfaces and solvent shielding for the pseudo-peptide. The docked conformation of 2-mercapto-3-phenylpropionyl-RATKML was then used to refine our pharmacophore for botulinum serotype A light chain inhibition. Data base search queries derived from the pharmacophore were employed to mine small molecule (non-peptidic) inhibitors from the National Cancer Institute's Open Repository. Four of the inhibitors possess K, values ranging from 3.0 to 10.0 mu m. Of these, NSC 240898 is a promising lead for therapeutic development, as it readily enters neurons, exhibits no neuronal toxicity, and elicits dose-dependent protection of synaptosomal-associated protein (of 25 kDa) in a primary culture of embryonic chicken neurons. Isothermal titration calorimetry showed that the interaction between NSC 240898 and the botulinum A light chain is largely entropy-driven, and occurs with a 1:1 stoichiometry and a dissociation constant of 4.6 mu M.

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External Sources

  1. DOI: 10.1074/jbc.M608166200
  2. WOS: 000244482000083

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