PMID:12121656
| Citation |
Powers, RA, Morandi, F and Shoichet, BK (2002) Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase. Structure 10:1013-23 |
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| Abstract |
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 microM or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive noncovalent inhibitor (K(i) = 26 microM), 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 A 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. |
| Links | |
| Keywords |
Ampicillin/pharmacology; Aniline Compounds/chemistry; Aniline Compounds/pharmacology; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Bacterial Proteins; Crystallography, X-Ray; Drug Design; Drug Resistance, Bacterial; Drug Synergism; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology; Escherichia coli/drug effects; Microbial Sensitivity Tests; Structure-Activity Relationship; Thiophenes/chemistry; Thiophenes/pharmacology; beta-Lactamases/antagonists & inhibitors |
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