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| {{STRUCTURE_2ish| PDB=2ish | SCENE= }} | | {{STRUCTURE_2ish| PDB=2ish | SCENE= }} |
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| '''Botulinum Neurotoxin A Light Chain WT Crystal Form C'''
| | ===Botulinum Neurotoxin A Light Chain WT Crystal Form C=== |
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| ==Overview==
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| 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(i) values ranging from 3.0 to 10.0 microM. 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 microM.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17092934}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17092934 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17092934}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Stegmann, C M.]] | | [[Category: Stegmann, C M.]] |
| [[Category: Botulinum neurotoxin]] | | [[Category: Botulinum neurotoxin]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:48:55 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 21:00:37 2008'' |