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Bioorg Med Chem. 2009 Feb 1;17(3):1079-87. doi: 10.1016/j.bmc.2008.02.046. Epub 2008 Feb 16.

ATP competitive inhibitors of D-alanine-D-alanine ligase based on protein kinase inhibitor scaffolds.

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Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto Hahn Strasse 11, 44227 Dortmund, Germany.


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.

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