Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors
A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (9), p.2585-2589 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 23 |
| creator | Stammers, Timothy A. Coulombe, René Rancourt, Jean Thavonekham, Bounkham Fazal, Gulrez Goulet, Sylvie Jakalian, Araz Wernic, Dominic Tsantrizos, Youla Poupart, Marc-André Bös, Michael McKercher, Ginette Thauvette, Louise Kukolj, George Beaulieu, Pierre L. |
| description | A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a–c and 12a–c from a weak-binding fragment-like structure 1 as a starting point. |
| doi_str_mv | 10.1016/j.bmcl.2013.02.110 |
| format | Article |
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Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a–c and 12a–c from a weak-binding fragment-like structure 1 as a starting point.</description><subject>Antiviral</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Binding Sites</subject><subject>Caco-2 Cells</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Drug Evaluation, Preclinical</subject><subject>drugs</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - enzymology</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>Non-nucleoside inhibitor</subject><subject>NS5B polymerase</subject><subject>Nucleosides - chemistry</subject><subject>ortho-Aminobenzoates - chemistry</subject><subject>Parallel synthesis</subject><subject>Protein Structure, Tertiary</subject><subject>Structure based drug design</subject><subject>Structure-Activity Relationship</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>X-ray diffraction</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi0EokvhD3AAH7kkjL_iROJCl48iVXAoRUgcLMeeUC9JvNhJpf33eLWFI6cZjZ55NfMQ8pxBzYA1r3d1P7mx5sBEDbxmDB6QDZONrIQE9ZBsoGugajv5_Yw8yXkHwCRI-ZiccaGkYtBuyI93Ibt4h-lA40AtnUs_0owpYD5O5jhX8-pGjDl4pMvtOvV0H90vXCinl9tv9PO1uiiT8TBhshlpmG9DH5aY8lPyaLBjxmf39ZzcfHj_dXtZXX35-Gn79qpyooWl0g3rBTa-sx4H5UErbRlvLfe8930HjZBWee5Z7wbZeZSCsUELLrnS0EonzsmrU-4-xd8r5sVM5SkcRztjXLNhgmvNpeaioPyEuhRzTjiYfQqTTQfDwBylmp05SjVHqQa4KVLL0ov7_LWf0P9b-WuxAC9PwGCjsT9TyObmuiSoYlywTupCvDkRWDzcBUwmu4CzQx8SusX4GP53wR8VKZCL</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Stammers, Timothy A.</creator><creator>Coulombe, René</creator><creator>Rancourt, Jean</creator><creator>Thavonekham, Bounkham</creator><creator>Fazal, Gulrez</creator><creator>Goulet, Sylvie</creator><creator>Jakalian, Araz</creator><creator>Wernic, Dominic</creator><creator>Tsantrizos, Youla</creator><creator>Poupart, Marc-André</creator><creator>Bös, Michael</creator><creator>McKercher, Ginette</creator><creator>Thauvette, Louise</creator><creator>Kukolj, George</creator><creator>Beaulieu, Pierre L.</creator><general>Elsevier Ltd</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20130501</creationdate><title>Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors</title><author>Stammers, Timothy A. ; Coulombe, René ; Rancourt, Jean ; Thavonekham, Bounkham ; Fazal, Gulrez ; Goulet, Sylvie ; Jakalian, Araz ; Wernic, Dominic ; Tsantrizos, Youla ; Poupart, Marc-André ; Bös, Michael ; McKercher, Ginette ; Thauvette, Louise ; Kukolj, George ; Beaulieu, Pierre L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-761b3e6d9adef5d0757a128a2d2bdb90634a5d2d1bcf49de4311f7324257084c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antiviral</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Binding Sites</topic><topic>Caco-2 Cells</topic><topic>Cell Membrane Permeability - drug effects</topic><topic>chemistry</topic><topic>Crystallography, X-Ray</topic><topic>Drug Evaluation, Preclinical</topic><topic>drugs</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Hepacivirus - drug effects</topic><topic>Hepacivirus - enzymology</topic><topic>Hepatitis C virus</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>Non-nucleoside inhibitor</topic><topic>NS5B polymerase</topic><topic>Nucleosides - chemistry</topic><topic>ortho-Aminobenzoates - chemistry</topic><topic>Parallel synthesis</topic><topic>Protein Structure, Tertiary</topic><topic>Structure based drug design</topic><topic>Structure-Activity Relationship</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - metabolism</topic><topic>X-ray diffraction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stammers, Timothy A.</creatorcontrib><creatorcontrib>Coulombe, René</creatorcontrib><creatorcontrib>Rancourt, Jean</creatorcontrib><creatorcontrib>Thavonekham, Bounkham</creatorcontrib><creatorcontrib>Fazal, Gulrez</creatorcontrib><creatorcontrib>Goulet, Sylvie</creatorcontrib><creatorcontrib>Jakalian, Araz</creatorcontrib><creatorcontrib>Wernic, Dominic</creatorcontrib><creatorcontrib>Tsantrizos, Youla</creatorcontrib><creatorcontrib>Poupart, Marc-André</creatorcontrib><creatorcontrib>Bös, Michael</creatorcontrib><creatorcontrib>McKercher, Ginette</creatorcontrib><creatorcontrib>Thauvette, Louise</creatorcontrib><creatorcontrib>Kukolj, George</creatorcontrib><creatorcontrib>Beaulieu, Pierre L.</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>Stammers, Timothy A.</au><au>Coulombe, René</au><au>Rancourt, Jean</au><au>Thavonekham, Bounkham</au><au>Fazal, Gulrez</au><au>Goulet, Sylvie</au><au>Jakalian, Araz</au><au>Wernic, Dominic</au><au>Tsantrizos, Youla</au><au>Poupart, Marc-André</au><au>Bös, Michael</au><au>McKercher, Ginette</au><au>Thauvette, Louise</au><au>Kukolj, George</au><au>Beaulieu, Pierre L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>23</volume><issue>9</issue><spage>2585</spage><epage>2589</epage><pages>2585-2589</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. 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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (9), p.2585-2589 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Antiviral Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Binding Sites Caco-2 Cells Cell Membrane Permeability - drug effects chemistry Crystallography, X-Ray Drug Evaluation, Preclinical drugs Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Hepacivirus - drug effects Hepacivirus - enzymology Hepatitis C virus Humans Molecular Docking Simulation Non-nucleoside inhibitor NS5B polymerase Nucleosides - chemistry ortho-Aminobenzoates - chemistry Parallel synthesis Protein Structure, Tertiary Structure based drug design Structure-Activity Relationship Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism X-ray diffraction |
| title | Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors |
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