Download MendeleyStructure-based optimization of cephalothin-analogue boronic acids as beta-lactamase inhibitors
Morandi, S., Morandi, F., Caselli, E., Shoichet, B.K., Prati, F.(2008) Bioorg Med Chem 16: 1195-1205
- PubMed: 17997318
- DOI: https://doi.org/10.1016/j.bmc.2007.10.075
- Primary Citation of Related Structures:
2RCX - PubMed Abstract:
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 beta-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.
Organizational Affiliation:
Dipartimento di Chimica, Università degli studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy.
