Structure-based approach for identification of novel phenylboronic acids as serine-[beta]-lactamase inhibitors
[beta]-Lactamases are bacterial enzymes conferring resistance to [beta]-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...
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Veröffentlicht in: | Journal of computer-aided molecular design 2016-10, Vol.30 (10), p.851 |
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creator | Sgrignani, Jacopo De Luca, Filomena Torosyan, Hayarpi Docquier, Jean-denis Duan, Da Novati, Beatrice Prati, Fabio Colombo, Giorgio Grazioso, Giovanni |
description | [beta]-Lactamases are bacterial enzymes conferring resistance to [beta]-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 [beta]-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant [beta]-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K i 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. |
doi_str_mv | 10.1007/s10822-016-9962-8 |
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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 [beta]-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant [beta]-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K i 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.</description><identifier>ISSN: 0920-654X</identifier><identifier>EISSN: 1573-4951</identifier><identifier>DOI: 10.1007/s10822-016-9962-8</identifier><language>eng</language><publisher>Dordrecht: Springer Nature B.V</publisher><subject>Antibiotics ; Bacterial proteins ; CAD ; Computer aided design ; Drug resistance ; Enzymes ; Inhibitors ; Molecular structure</subject><ispartof>Journal of computer-aided molecular design, 2016-10, Vol.30 (10), p.851</ispartof><rights>Springer International Publishing Switzerland 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Sgrignani, Jacopo</creatorcontrib><creatorcontrib>De Luca, Filomena</creatorcontrib><creatorcontrib>Torosyan, Hayarpi</creatorcontrib><creatorcontrib>Docquier, Jean-denis</creatorcontrib><creatorcontrib>Duan, Da</creatorcontrib><creatorcontrib>Novati, Beatrice</creatorcontrib><creatorcontrib>Prati, Fabio</creatorcontrib><creatorcontrib>Colombo, Giorgio</creatorcontrib><creatorcontrib>Grazioso, Giovanni</creatorcontrib><title>Structure-based approach for identification of novel phenylboronic acids as serine-[beta]-lactamase inhibitors</title><title>Journal of computer-aided molecular design</title><description>[beta]-Lactamases are bacterial enzymes conferring resistance to [beta]-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. 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subjects | Antibiotics Bacterial proteins CAD Computer aided design Drug resistance Enzymes Inhibitors Molecular structure |
title | Structure-based approach for identification of novel phenylboronic acids as serine-[beta]-lactamase inhibitors |
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