title: Structure-based optimization of cephalothin-analogue boronic acids as beta-lactamase inhibitors.
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.
authors.affiliation: Dipartimento di Chimica, Università degli studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Morandi
authors.forename: Federica
authors.initials: F
authors.lastname: Morandi
authors.forename: Emilia
authors.initials: E
authors.lastname: Caselli
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: Fabio
authors.initials: F
authors.lastname: Prati
mesh_terms: D001665:Binding Sites; D001897:Boronic Acids / Q000737:chemistry*; D002512:Cephalothin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D002512:Cephalothin