期刊
STRUCTURE
卷 10, 期 7, 页码 1013-1023出版社
CELL PRESS
DOI: 10.1016/S0969-2126(02)00799-2
关键词
-
资金
- NIGMS NIH HHS [GM63815, GM59953] Funding Source: Medline
beta-lactamases are the most widespread resistance mechanisms to beta-lactam antibiotics, and there is a pressing need for novel, non-beta-lactam drugs. A database of over 200,000 compounds was docked to the active site of AmpC beta-lactamase to identify potential inhibitors. Fifty-six compounds were tested, and three had K-i values of 650 muM or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive noncovalent inhibitor (K-i = 26 muM), which also reversed resistance to beta-lactams in bacteria expressing AmpC. The structure of AmpC in complex with this compound was determined by X-ray crystallography to 1.94 Angstrom and reveals that the inhibitor interacts with key active-site residues in sites targeted in the docking calculation. Indeed, the experimentally determined conformation of the inhibitor closely resembles the prediction. The structure of the enzyme-inhibitor complex presents an opportunity to improve binding affinity in a novel series of inhibitors discovered by structure-based methods.
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