ATP competitive inhibitors of D-alanine-D-alanine ligase based on protein kinase inhibitor scaffolds.
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.
Triola
Gemma
G
Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto Hahn Strasse 11, 44227 Dortmund, Germany.
Wetzel
Stefan
S
Ellinger
Bernhard
B
Koch
Marcus A
MA
Hübel
Katja
K
Rauh
Daniel
D
Waldmann
Herbert
H
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry; D000077339:Leflunomide; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D000900:Anti-Bacterial Agents; D007555:Isoxazoles; C118451:LFM A13; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D012459:Salicylates; D000255:Adenosine Triphosphate; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase; D000077339:Leflunomide