Abstract
D-Alanine-D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons's tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a K(i) of 185 microM. A series of malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / chemistry*
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Amides / chemical synthesis
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Amides / chemistry*
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Amides / pharmacology
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / pharmacology
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Binding Sites
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Isoxazoles / chemical synthesis
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Isoxazoles / chemistry
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Leflunomide
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Nitriles / chemical synthesis
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Nitriles / chemistry*
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Nitriles / pharmacology
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Peptide Synthases / antagonists & inhibitors*
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Peptide Synthases / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Salicylates / chemical synthesis
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Salicylates / chemistry
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Structure-Activity Relationship
Substances
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Amides
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Anti-Bacterial Agents
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Isoxazoles
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LFM A13
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Nitriles
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Protein Kinase Inhibitors
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Salicylates
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Adenosine Triphosphate
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Peptide Synthases
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D-alanylalanine synthetase
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Leflunomide