Article (Scientific journals)
Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors
Sgrignani, J.; De Luca, F.; Torosyan, H. et al.
2016In Journal of Computer-Aided Molecular Design, 30 (10), p. 851-861
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Keywords :
Antibiotic resistance; Beta-lactamase; Boronic acids; Carbapenemase; Docking; Extended-spectrum β-lactamase; Virtual screening; AmpC beta-lactamases; Article; Enterobacter; Escherichia coli; Bacterial Proteins; Binding Sites; Computer Simulation; Drug Discovery; Models, Molecular; Protein Binding; Protein Conformation; Serine
Abstract :
[en] β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of ~1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar Ki value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase. © 2016, Springer International Publishing Switzerland.
Disciplines :
Microbiology
Biochemistry, biophysics & molecular biology
Author, co-author :
Sgrignani, J.;  ICRM-CNR, Via Mario Bianco 9, Milan, 20131, Italy, Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI), Via Vincenzo Vela 6, Bellinzona, 6500, Switzerland
De Luca, F.;  Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico “Le Scotte”, Viale Bracci 16, Siena, 53100, Italy
Torosyan, H.;  Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Byers Hall, San Francisco, CA 94158, United States
Docquier, Jean-Denis ;  Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines
Duan, D.;  Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Byers Hall, San Francisco, CA 94158, United States
Novati, B.;  Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, Milan, 20133, Italy
Prati, F.;  Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via G. Campi 103, Modena, 41125, Italy
Colombo, G.;  ICRM-CNR, Via Mario Bianco 9, Milan, 20131, Italy
Grazioso, G.;  Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, Milan, 20133, Italy
Language :
English
Title :
Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors
Publication date :
2016
Journal title :
Journal of Computer-Aided Molecular Design
ISSN :
0920-654X
eISSN :
1573-4951
Publisher :
Springer International Publishing
Volume :
30
Issue :
10
Pages :
851-861
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Regione Lombardia
AIRC - Associazione Italiana per la Ricerca sul Cancro [IT]
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