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.

Structure-based optimization of cephalotin analogue boronic acids as beta-lactamase inhibitors / Morandi, Stefania; Morandi, Federica; Caselli, Emilia; B. K., Shoichet; Prati, Fabio. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 16:3(2008), pp. 1195-1205. [10.1016/j.bmc.2007.10.075]

Structure-based optimization of cephalotin analogue boronic acids as beta-lactamase inhibitors

MORANDI, Stefania;MORANDI, federica;CASELLI, Emilia;PRATI, Fabio
2008

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.
2008
16
3
1195
1205
Structure-based optimization of cephalotin analogue boronic acids as beta-lactamase inhibitors / Morandi, Stefania; Morandi, Federica; Caselli, Emilia; B. K., Shoichet; Prati, Fabio. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 16:3(2008), pp. 1195-1205. [10.1016/j.bmc.2007.10.075]
Morandi, Stefania; Morandi, Federica; Caselli, Emilia; B. K., Shoichet; Prati, Fabio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/585413
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