期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 3, 页码 1195-1205出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2007.10.075
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资金
- NIGMS NIH HHS [R01 GM063815-07, GM63815, R01 GM063815] Funding Source: Medline
Boronic acids have proved to be promising selective inhibitors of beta-lactamases, acting as transition state analogues. Starting from a previously described nanomolar inhibitor of AmpC P-lactamase, three new inhibitors were designed to gain interactions with highly conserved residues, such as Asn343, and to bind more tightly to the enzyme. Among these, one was obtained by stereoselective synthesis and succeeded in placing its anionic group into the carboxylate binding site of the enzyme, as revealed by X-ray crystallography of the complex inhibitor/AmpC. Nevertheless, it failed at improving affinity, when compared to the lead from which it was derived. The origins of this structural and energetic discrepancy are discussed. (c) 2007 Elsevier Ltd. All rights reserved.
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