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Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity
The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor developm...
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| Published in: | Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (5), p.1529-1536 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| cited_by | cdi_FETCH-LOGICAL-c380t-f384557a7303946c15f9293890f540be0d23e333eb910a02cf121e7558021c6b3 |
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| cites | cdi_FETCH-LOGICAL-c380t-f384557a7303946c15f9293890f540be0d23e333eb910a02cf121e7558021c6b3 |
| container_end_page | 1536 |
| container_issue | 5 |
| container_start_page | 1529 |
| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Tari, Leslie W. Trzoss, Michael Bensen, Daniel C. Li, Xiaoming Chen, Zhiyong Lam, Thanh Zhang, Junhu Creighton, Christopher J. Cunningham, Mark L. Kwan, Bryan Stidham, Mark Shaw, Karen J. Lightstone, Felice C. Wong, Sergio E. Nguyen, Toan B. Nix, Jay Finn, John |
| description | The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity. |
| doi_str_mv | 10.1016/j.bmcl.2012.11.032 |
| format | article |
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The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. 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Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity</title><author>Tari, Leslie W. ; Trzoss, Michael ; Bensen, Daniel C. ; Li, Xiaoming ; Chen, Zhiyong ; Lam, Thanh ; Zhang, Junhu ; Creighton, Christopher J. ; Cunningham, Mark L. ; Kwan, Bryan ; Stidham, Mark ; Shaw, Karen J. ; Lightstone, Felice C. ; Wong, Sergio E. ; Nguyen, Toan B. ; Nix, Jay ; Finn, John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-f384557a7303946c15f9293890f540be0d23e333eb910a02cf121e7558021c6b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Bacterial topoisomerases</topic><topic>chemistry</topic><topic>DNA</topic><topic>DNA Gyrase - metabolism</topic><topic>DNA topoisomerase</topic><topic>DNA topoisomerase (ATP-hydrolysing)</topic><topic>DNA Topoisomerase IV - antagonists & inhibitors</topic><topic>DNA Topoisomerase IV - chemistry</topic><topic>Drug Design</topic><topic>enzyme activity</topic><topic>GyrB</topic><topic>Inhibitor</topic><topic>Models, Molecular</topic><topic>ParE</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrrolopyrimidine</topic><topic>Structure-Activity Relationship</topic><topic>Topoisomerase II Inhibitors - chemistry</topic><topic>Topoisomerase II Inhibitors - pharmacology</topic><topic>topology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tari, Leslie W.</creatorcontrib><creatorcontrib>Trzoss, Michael</creatorcontrib><creatorcontrib>Bensen, Daniel C.</creatorcontrib><creatorcontrib>Li, Xiaoming</creatorcontrib><creatorcontrib>Chen, Zhiyong</creatorcontrib><creatorcontrib>Lam, Thanh</creatorcontrib><creatorcontrib>Zhang, Junhu</creatorcontrib><creatorcontrib>Creighton, Christopher J.</creatorcontrib><creatorcontrib>Cunningham, Mark L.</creatorcontrib><creatorcontrib>Kwan, Bryan</creatorcontrib><creatorcontrib>Stidham, Mark</creatorcontrib><creatorcontrib>Shaw, Karen J.</creatorcontrib><creatorcontrib>Lightstone, Felice C.</creatorcontrib><creatorcontrib>Wong, Sergio E.</creatorcontrib><creatorcontrib>Nguyen, Toan B.</creatorcontrib><creatorcontrib>Nix, Jay</creatorcontrib><creatorcontrib>Finn, John</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tari, Leslie W.</au><au>Trzoss, Michael</au><au>Bensen, Daniel C.</au><au>Li, Xiaoming</au><au>Chen, Zhiyong</au><au>Lam, Thanh</au><au>Zhang, Junhu</au><au>Creighton, Christopher J.</au><au>Cunningham, Mark L.</au><au>Kwan, Bryan</au><au>Stidham, Mark</au><au>Shaw, Karen J.</au><au>Lightstone, Felice C.</au><au>Wong, Sergio E.</au><au>Nguyen, Toan B.</au><au>Nix, Jay</au><au>Finn, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>23</volume><issue>5</issue><spage>1529</spage><epage>1536</epage><pages>1529-1536</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><notes>http://dx.doi.org/10.1016/j.bmcl.2012.11.032</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23352267</pmid><doi>10.1016/j.bmcl.2012.11.032</doi><tpages>8</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2013-03, Vol.23 (5), p.1529-1536 |
| issn | 0960-894X 1464-3405 |
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| source | ScienceDirect Freedom Collection |
| subjects | Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Bacterial topoisomerases chemistry DNA DNA Gyrase - metabolism DNA topoisomerase DNA topoisomerase (ATP-hydrolysing) DNA Topoisomerase IV - antagonists & inhibitors DNA Topoisomerase IV - chemistry Drug Design enzyme activity GyrB Inhibitor Models, Molecular ParE Pyrimidines - chemistry Pyrimidines - pharmacology Pyrroles - chemistry Pyrroles - pharmacology Pyrrolopyrimidine Structure-Activity Relationship Topoisomerase II Inhibitors - chemistry Topoisomerase II Inhibitors - pharmacology topology |
| title | Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity |
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