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Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA
Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA...
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| Published in: | Angewandte Chemie 2015-08, Vol.127 (35), p.10382-10386 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c1725-ce5cdb39e45bcc948f60aa32857feae6b83349fee140b495ee0124d8bb53a2623 |
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| cites | cdi_FETCH-LOGICAL-c1725-ce5cdb39e45bcc948f60aa32857feae6b83349fee140b495ee0124d8bb53a2623 |
| container_end_page | 10386 |
| container_issue | 35 |
| container_start_page | 10382 |
| container_title | Angewandte Chemie |
| container_volume | 127 |
| creator | Perna, Anna M. Rodrigues, Tiago Schmidt, Thomas P. Böhm, Manja Stutz, Katharina Reker, Daniel Pfeiffer, Bernhard Altmann, Karl-Heinz Backert, Steffen Wessler, Silja Schneider, Gisbert |
| description | Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best‐in‐class HtrA inhibitor. The results obtained reinforce the validity of ligand‐based de novo design and binding‐kinetics‐guided optimization for the efficient discovery of pioneering lead structures and prototyping drug‐like chemical probes with tailored bioactivity.
Der derzeit beste seiner Klasse ist ein Inhibitor von Helicobacter pylori HtrA, der durch fragmentbasiertes De‐novo‐Design und Analogasynthese ermittelt wurde. So lassen sich neue chemische Prototypen rasch ermitteln, und der neue Inhibitor ist ein derartiges innovatives Hilfsmittel für die chemische Biologie und eine mögliche Leitstruktur für die Suche nach Tumortherapeutika und Antiinfektiva. |
| doi_str_mv | 10.1002/ange.201504035 |
| format | article |
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Der derzeit beste seiner Klasse ist ein Inhibitor von Helicobacter pylori HtrA, der durch fragmentbasiertes De‐novo‐Design und Analogasynthese ermittelt wurde. So lassen sich neue chemische Prototypen rasch ermitteln, und der neue Inhibitor ist ein derartiges innovatives Hilfsmittel für die chemische Biologie und eine mögliche Leitstruktur für die Suche nach Tumortherapeutika und Antiinfektiva.</description><identifier>ISSN: 0044-8249</identifier><identifier>EISSN: 1521-3757</identifier><identifier>DOI: 10.1002/ange.201504035</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>Biophysikalische Methoden ; Chemische Biologie ; Computergestütztes Wirkstoff-Design ; Rezeptor-Ligand-Wechselwirkungen ; Wirkstoff-Design</subject><ispartof>Angewandte Chemie, 2015-08, Vol.127 (35), p.10382-10386</ispartof><rights>2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1725-ce5cdb39e45bcc948f60aa32857feae6b83349fee140b495ee0124d8bb53a2623</citedby><cites>FETCH-LOGICAL-c1725-ce5cdb39e45bcc948f60aa32857feae6b83349fee140b495ee0124d8bb53a2623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27922,27923</link.rule.ids></links><search><creatorcontrib>Perna, Anna M.</creatorcontrib><creatorcontrib>Rodrigues, Tiago</creatorcontrib><creatorcontrib>Schmidt, Thomas P.</creatorcontrib><creatorcontrib>Böhm, Manja</creatorcontrib><creatorcontrib>Stutz, Katharina</creatorcontrib><creatorcontrib>Reker, Daniel</creatorcontrib><creatorcontrib>Pfeiffer, Bernhard</creatorcontrib><creatorcontrib>Altmann, Karl-Heinz</creatorcontrib><creatorcontrib>Backert, Steffen</creatorcontrib><creatorcontrib>Wessler, Silja</creatorcontrib><creatorcontrib>Schneider, Gisbert</creatorcontrib><title>Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA</title><title>Angewandte Chemie</title><addtitle>Angew. Chem</addtitle><description>Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best‐in‐class HtrA inhibitor. The results obtained reinforce the validity of ligand‐based de novo design and binding‐kinetics‐guided optimization for the efficient discovery of pioneering lead structures and prototyping drug‐like chemical probes with tailored bioactivity.
Der derzeit beste seiner Klasse ist ein Inhibitor von Helicobacter pylori HtrA, der durch fragmentbasiertes De‐novo‐Design und Analogasynthese ermittelt wurde. So lassen sich neue chemische Prototypen rasch ermitteln, und der neue Inhibitor ist ein derartiges innovatives Hilfsmittel für die chemische Biologie und eine mögliche Leitstruktur für die Suche nach Tumortherapeutika und Antiinfektiva.</description><subject>Biophysikalische Methoden</subject><subject>Chemische Biologie</subject><subject>Computergestütztes Wirkstoff-Design</subject><subject>Rezeptor-Ligand-Wechselwirkungen</subject><subject>Wirkstoff-Design</subject><issn>0044-8249</issn><issn>1521-3757</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNqF0DtPAkEQwPGN0UREW-v9Aoezr3uUiPJIAIlo7NzsLXO4etyZvROls_GL-kk8giF2VjPF_Kb4E3LOoMMA-IUpltjhwBRIEOqAtJjiLBCRig5JC0DKIOYyOSYnVfUMACGPkhZ57HuzXGFRB5emwgW9wu_Pr2m5LputcsuC3uIaTV5RQ-crk-fBpMzRvuVIR8WTS11delpmdIi5s2VqbI2ezjZ56R0d1r57So6yRuPZ72yT-_71XW8YjG8Go153HFgWcRVYVHaRigSlSq1NZJyFYIzgsYoyNBimsRAyyRCZhFQmChEYl4s4TZUwPOSiTTq7v9aXVeUx06_erYzfaAZ6W0dv6-h9nQYkO_Ductz8c62708H1XxvsrKtq_Nhb4190GDW99cN0oPtzkMMJzPRY_ACGsHl1</recordid><startdate>20150824</startdate><enddate>20150824</enddate><creator>Perna, Anna M.</creator><creator>Rodrigues, Tiago</creator><creator>Schmidt, Thomas P.</creator><creator>Böhm, Manja</creator><creator>Stutz, Katharina</creator><creator>Reker, Daniel</creator><creator>Pfeiffer, Bernhard</creator><creator>Altmann, Karl-Heinz</creator><creator>Backert, Steffen</creator><creator>Wessler, Silja</creator><creator>Schneider, Gisbert</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><scope>BSCLL</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20150824</creationdate><title>Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA</title><author>Perna, Anna M. ; Rodrigues, Tiago ; Schmidt, Thomas P. ; Böhm, Manja ; Stutz, Katharina ; Reker, Daniel ; Pfeiffer, Bernhard ; Altmann, Karl-Heinz ; Backert, Steffen ; Wessler, Silja ; Schneider, Gisbert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1725-ce5cdb39e45bcc948f60aa32857feae6b83349fee140b495ee0124d8bb53a2623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Biophysikalische Methoden</topic><topic>Chemische Biologie</topic><topic>Computergestütztes Wirkstoff-Design</topic><topic>Rezeptor-Ligand-Wechselwirkungen</topic><topic>Wirkstoff-Design</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Perna, Anna M.</creatorcontrib><creatorcontrib>Rodrigues, Tiago</creatorcontrib><creatorcontrib>Schmidt, Thomas P.</creatorcontrib><creatorcontrib>Böhm, Manja</creatorcontrib><creatorcontrib>Stutz, Katharina</creatorcontrib><creatorcontrib>Reker, Daniel</creatorcontrib><creatorcontrib>Pfeiffer, Bernhard</creatorcontrib><creatorcontrib>Altmann, Karl-Heinz</creatorcontrib><creatorcontrib>Backert, Steffen</creatorcontrib><creatorcontrib>Wessler, Silja</creatorcontrib><creatorcontrib>Schneider, Gisbert</creatorcontrib><collection>Istex</collection><collection>CrossRef</collection><jtitle>Angewandte Chemie</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Perna, Anna M.</au><au>Rodrigues, Tiago</au><au>Schmidt, Thomas P.</au><au>Böhm, Manja</au><au>Stutz, Katharina</au><au>Reker, Daniel</au><au>Pfeiffer, Bernhard</au><au>Altmann, Karl-Heinz</au><au>Backert, Steffen</au><au>Wessler, Silja</au><au>Schneider, Gisbert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA</atitle><jtitle>Angewandte Chemie</jtitle><addtitle>Angew. Chem</addtitle><date>2015-08-24</date><risdate>2015</risdate><volume>127</volume><issue>35</issue><spage>10382</spage><epage>10386</epage><pages>10382-10386</pages><issn>0044-8249</issn><eissn>1521-3757</eissn><abstract>Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best‐in‐class HtrA inhibitor. The results obtained reinforce the validity of ligand‐based de novo design and binding‐kinetics‐guided optimization for the efficient discovery of pioneering lead structures and prototyping drug‐like chemical probes with tailored bioactivity.
Der derzeit beste seiner Klasse ist ein Inhibitor von Helicobacter pylori HtrA, der durch fragmentbasiertes De‐novo‐Design und Analogasynthese ermittelt wurde. So lassen sich neue chemische Prototypen rasch ermitteln, und der neue Inhibitor ist ein derartiges innovatives Hilfsmittel für die chemische Biologie und eine mögliche Leitstruktur für die Suche nach Tumortherapeutika und Antiinfektiva.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><doi>10.1002/ange.201504035</doi><tpages>5</tpages></addata></record> |
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| language | eng |
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| source | Wiley:Jisc Collections:Wiley Read and Publish Open Access 2024-2025 (reading list) |
| subjects | Biophysikalische Methoden Chemische Biologie Computergestütztes Wirkstoff-Design Rezeptor-Ligand-Wechselwirkungen Wirkstoff-Design |
| title | Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA |
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