Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors
Identifieur interne : 000466 ( PascalFrancis/Checkpoint ); précédent : 000465; suivant : 000467Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors
Auteurs : HUI LI [États-Unis] ; John Tatlock [États-Unis] ; Angelica Linton [États-Unis] ; Javier Gonzalez [États-Unis] ; Allen Borchardt [États-Unis] ; Peter Dragovich [États-Unis] ; Tanya Jewell [États-Unis] ; Tom Prins [États-Unis] ; RU ZHOU [États-Unis] ; Julie Blazel [États-Unis] ; Hans Parge [États-Unis] ; Robert Love [États-Unis] ; Michael Hickey [États-Unis] ; Chau Doan [États-Unis] ; Stephanie Shi [États-Unis] ; Rohit Duggal [États-Unis] ; Cristina Lewis [États-Unis] ; Shella Fuhrman [États-Unis]Source :
- Bioorganic & medicinal chemistry letters : (Print) [ 0960-894X ] ; 2006.
Descripteurs français
- Pascal (Inist)
- Optimisation, Virus hépatite C, DNA-directed RNA polymerase, Inhibiteur enzyme, Composé non nucléoside, Criblage, Structure cristalline, Site fixation, Changement conformation, Relation structure activité, Pyranone dérivé, Cyclopentane dérivé, Lactone, Antiviral, Composé benzénique, Halogène Composé organique, RNA-directed RNA polymerase, Pyrane dérivé, NS5B polymerase, Pyran-2-one(3-[4-amino-2-(t-butyl)-5-méthylphénylsulfanyl]-6-cyclopentyl-5,6-dihydro-4-hydroxy-6-[4-hydroxyphénéthyl]), Pyrane-2,4-dione dérivé, Protéine NS5B.
English descriptors
- KwdEn :
- Antiviral, Benzenic compound, Binding site, Conformational changes, Crystalline structure, Cyclopentane derivatives, DNA-directed RNA polymerase, Enzyme inhibitor, Halogen Organic compounds, Hepatitis C virus, Lactone, Non nucleoside compound, Optimization, Pyran derivatives, Pyranone derivatives, RNA-directed RNA polymerase, Screening, Structure activity relation.
Abstract
A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.
Affiliations:
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Pascal:07-0028982Le document en format XML
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<author><name sortKey="Shi, Stephanie" sort="Shi, Stephanie" uniqKey="Shi S" first="Stephanie" last="Shi">Stephanie Shi</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors</title>
<author><name sortKey="Hui Li" sort="Hui Li" uniqKey="Hui Li" last="Hui Li">HUI LI</name>
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<author><name sortKey="Gonzalez, Javier" sort="Gonzalez, Javier" uniqKey="Gonzalez J" first="Javier" last="Gonzalez">Javier Gonzalez</name>
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<series><title level="j" type="main">Bioorganic & medicinal chemistry letters : (Print)</title>
<title level="j" type="abbreviated">Bioorg. med. chem. lett. : (Print)</title>
<idno type="ISSN">0960-894X</idno>
<imprint><date when="2006">2006</date>
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<title level="j" type="abbreviated">Bioorg. med. chem. lett. : (Print)</title>
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<term>Benzenic compound</term>
<term>Binding site</term>
<term>Conformational changes</term>
<term>Crystalline structure</term>
<term>Cyclopentane derivatives</term>
<term>DNA-directed RNA polymerase</term>
<term>Enzyme inhibitor</term>
<term>Halogen Organic compounds</term>
<term>Hepatitis C virus</term>
<term>Lactone</term>
<term>Non nucleoside compound</term>
<term>Optimization</term>
<term>Pyran derivatives</term>
<term>Pyranone derivatives</term>
<term>RNA-directed RNA polymerase</term>
<term>Screening</term>
<term>Structure activity relation</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Optimisation</term>
<term>Virus hépatite C</term>
<term>DNA-directed RNA polymerase</term>
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<term>Composé non nucléoside</term>
<term>Criblage</term>
<term>Structure cristalline</term>
<term>Site fixation</term>
<term>Changement conformation</term>
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<term>Cyclopentane dérivé</term>
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<term>NS5B polymerase</term>
<term>Pyran-2-one(3-[4-amino-2-(t-butyl)-5-méthylphénylsulfanyl]-6-cyclopentyl-5,6-dihydro-4-hydroxy-6-[4-hydroxyphénéthyl])</term>
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<front><div type="abstract" xml:lang="en">A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.</div>
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<fA08 i1="01" i2="1" l="ENG"><s1>Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors</s1>
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<s5>03</s5>
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<fC03 i1="03" i2="X" l="SPA"><s0>DNA-directed RNA polymerase</s0>
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<s5>03</s5>
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</fC03>
<fC03 i1="08" i2="X" l="ENG"><s0>Binding site</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Sitio fijación</s0>
<s5>08</s5>
</fC03>
<fC03 i1="09" i2="3" l="FRE"><s0>Changement conformation</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="3" l="ENG"><s0>Conformational changes</s0>
<s5>09</s5>
</fC03>
<fC03 i1="10" i2="X" l="FRE"><s0>Relation structure activité</s0>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="ENG"><s0>Structure activity relation</s0>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA"><s0>Relación estructura actividad</s0>
<s5>10</s5>
</fC03>
<fC03 i1="11" i2="X" l="FRE"><s0>Pyranone dérivé</s0>
<s2>FR</s2>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="ENG"><s0>Pyranone derivatives</s0>
<s2>FR</s2>
<s5>11</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE"><s0>Cyclopentane dérivé</s0>
<s5>12</s5>
</fC03>
<fC03 i1="12" i2="X" l="ENG"><s0>Cyclopentane derivatives</s0>
<s5>12</s5>
</fC03>
<fC03 i1="12" i2="X" l="SPA"><s0>Ciclopentano derivado</s0>
<s5>12</s5>
</fC03>
<fC03 i1="13" i2="X" l="FRE"><s0>Lactone</s0>
<s5>13</s5>
</fC03>
<fC03 i1="13" i2="X" l="ENG"><s0>Lactone</s0>
<s5>13</s5>
</fC03>
<fC03 i1="13" i2="X" l="SPA"><s0>Lactona</s0>
<s5>13</s5>
</fC03>
<fC03 i1="14" i2="X" l="FRE"><s0>Antiviral</s0>
<s5>14</s5>
</fC03>
<fC03 i1="14" i2="X" l="ENG"><s0>Antiviral</s0>
<s5>14</s5>
</fC03>
<fC03 i1="14" i2="X" l="SPA"><s0>Antiviral</s0>
<s5>14</s5>
</fC03>
<fC03 i1="15" i2="X" l="FRE"><s0>Composé benzénique</s0>
<s5>15</s5>
</fC03>
<fC03 i1="15" i2="X" l="ENG"><s0>Benzenic compound</s0>
<s5>15</s5>
</fC03>
<fC03 i1="15" i2="X" l="SPA"><s0>Compuesto bencénico</s0>
<s5>15</s5>
</fC03>
<fC03 i1="16" i2="X" l="FRE"><s0>Halogène Composé organique</s0>
<s2>NC</s2>
<s2>NA</s2>
<s5>16</s5>
</fC03>
<fC03 i1="16" i2="X" l="ENG"><s0>Halogen Organic compounds</s0>
<s2>NC</s2>
<s2>NA</s2>
<s5>16</s5>
</fC03>
<fC03 i1="16" i2="X" l="SPA"><s0>Halógeno Compuesto orgánico</s0>
<s2>NC</s2>
<s2>NA</s2>
<s5>16</s5>
</fC03>
<fC03 i1="17" i2="X" l="FRE"><s0>RNA-directed RNA polymerase</s0>
<s2>FE</s2>
<s5>32</s5>
</fC03>
<fC03 i1="17" i2="X" l="ENG"><s0>RNA-directed RNA polymerase</s0>
<s2>FE</s2>
<s5>32</s5>
</fC03>
<fC03 i1="17" i2="X" l="SPA"><s0>RNA-directed RNA polymerase</s0>
<s2>FE</s2>
<s5>32</s5>
</fC03>
<fC03 i1="18" i2="X" l="FRE"><s0>Pyrane dérivé</s0>
<s5>33</s5>
</fC03>
<fC03 i1="18" i2="X" l="ENG"><s0>Pyran derivatives</s0>
<s5>33</s5>
</fC03>
<fC03 i1="18" i2="X" l="SPA"><s0>Pirano derivado</s0>
<s5>33</s5>
</fC03>
<fC03 i1="19" i2="X" l="FRE"><s0>NS5B polymerase</s0>
<s4>INC</s4>
<s5>76</s5>
</fC03>
<fC03 i1="20" i2="X" l="FRE"><s0>Pyran-2-one(3-[4-amino-2-(t-butyl)-5-méthylphénylsulfanyl]-6-cyclopentyl-5,6-dihydro-4-hydroxy-6-[4-hydroxyphénéthyl])</s0>
<s2>NK</s2>
<s4>INC</s4>
<s5>77</s5>
</fC03>
<fC03 i1="21" i2="X" l="FRE"><s0>Pyrane-2,4-dione dérivé</s0>
<s2>NK</s2>
<s4>INC</s4>
<s5>78</s5>
</fC03>
<fC03 i1="22" i2="X" l="FRE"><s0>Protéine NS5B</s0>
<s4>INC</s4>
<s5>91</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Hepacivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Hepacivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Hepacivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Flaviviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Flaviviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Flaviviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Nucleotidyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Nucleotidyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Nucleotidyltransferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="06" i2="X" l="FRE"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="06" i2="X" l="ENG"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Enzima</s0>
<s2>FE</s2>
</fC07>
<fN21><s1>015</s1>
</fN21>
</pA>
</standard>
</inist>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Californie</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Californie"><name sortKey="Hui Li" sort="Hui Li" uniqKey="Hui Li" last="Hui Li">HUI LI</name>
</region>
<name sortKey="Blazel, Julie" sort="Blazel, Julie" uniqKey="Blazel J" first="Julie" last="Blazel">Julie Blazel</name>
<name sortKey="Borchardt, Allen" sort="Borchardt, Allen" uniqKey="Borchardt A" first="Allen" last="Borchardt">Allen Borchardt</name>
<name sortKey="Doan, Chau" sort="Doan, Chau" uniqKey="Doan C" first="Chau" last="Doan">Chau Doan</name>
<name sortKey="Dragovich, Peter" sort="Dragovich, Peter" uniqKey="Dragovich P" first="Peter" last="Dragovich">Peter Dragovich</name>
<name sortKey="Duggal, Rohit" sort="Duggal, Rohit" uniqKey="Duggal R" first="Rohit" last="Duggal">Rohit Duggal</name>
<name sortKey="Fuhrman, Shella" sort="Fuhrman, Shella" uniqKey="Fuhrman S" first="Shella" last="Fuhrman">Shella Fuhrman</name>
<name sortKey="Gonzalez, Javier" sort="Gonzalez, Javier" uniqKey="Gonzalez J" first="Javier" last="Gonzalez">Javier Gonzalez</name>
<name sortKey="Hickey, Michael" sort="Hickey, Michael" uniqKey="Hickey M" first="Michael" last="Hickey">Michael Hickey</name>
<name sortKey="Jewell, Tanya" sort="Jewell, Tanya" uniqKey="Jewell T" first="Tanya" last="Jewell">Tanya Jewell</name>
<name sortKey="Lewis, Cristina" sort="Lewis, Cristina" uniqKey="Lewis C" first="Cristina" last="Lewis">Cristina Lewis</name>
<name sortKey="Linton, Angelica" sort="Linton, Angelica" uniqKey="Linton A" first="Angelica" last="Linton">Angelica Linton</name>
<name sortKey="Love, Robert" sort="Love, Robert" uniqKey="Love R" first="Robert" last="Love">Robert Love</name>
<name sortKey="Parge, Hans" sort="Parge, Hans" uniqKey="Parge H" first="Hans" last="Parge">Hans Parge</name>
<name sortKey="Prins, Tom" sort="Prins, Tom" uniqKey="Prins T" first="Tom" last="Prins">Tom Prins</name>
<name sortKey="Ru Zhou" sort="Ru Zhou" uniqKey="Ru Zhou" last="Ru Zhou">RU ZHOU</name>
<name sortKey="Shi, Stephanie" sort="Shi, Stephanie" uniqKey="Shi S" first="Stephanie" last="Shi">Stephanie Shi</name>
<name sortKey="Tatlock, John" sort="Tatlock, John" uniqKey="Tatlock J" first="John" last="Tatlock">John Tatlock</name>
</country>
</tree>
</affiliations>
</record>
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