A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods
Identifieur interne : 000538 ( PascalFrancis/Corpus ); précédent : 000537; suivant : 000539A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods
Auteurs : Ulrich Kaeppler ; Nikolaus Stiefl ; Markus Schiller ; Radim Vicik ; Alexander Breuning ; Werner Schmitz ; Daniel Rupprecht ; Carsten Schmuck ; Knut Baumann ; John Ziebuhr ; Tanja SchirmeisterSource :
- Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2005.
Descripteurs français
- Pascal (Inist)
- Composé non peptide, Site actif, Inhibiteur enzyme, Virus syndrome respiratoire aigu sévère, Peptidases, Synthèse chimique, Modèle moléculaire, Modélisation, Prédiction, Relation structure activité, Antiviral, Inhibiteur protease, Complexe enzyme inhibiteur, Enone, Benzène dérivé, Carboxamide, Ether, In vitro, Mode liaison, Etacrynique acide amide.
English descriptors
- KwdEn :
- Active site, Antiviral, Benzene derivatives, Binding mode, Carboxamide, Chemical synthesis, Enone, Enzyme inhibitor, Ether, In vitro, Inhibitor enzyme complex, Modeling, Molecular model, Non peptide compound, Peptidases, Prediction, Protease inhibitor, Severe acute respiratory syndrome virus, Structure activity relation.
Abstract
The coronavirus main protease, Mpro, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential Mpro inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed Mpro inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K1 value of 35.3 μM. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.
Notice en format standard (ISO 2709)
Pour connaître la documentation sur le format Inist Standard.
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Format Inist (serveur)
| NO : | PASCAL 06-0152074 INIST |
|---|---|
| ET : | A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods |
| AU : | KAEPPLER (Ulrich); STIEFL (Nikolaus); SCHILLER (Markus); VICIK (Radim); BREUNING (Alexander); SCHMITZ (Werner); RUPPRECHT (Daniel); SCHMUCK (Carsten); BAUMANN (Knut); ZIEBUHR (John); SCHIRMEISTER (Tanja) |
| AF : | Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland/97074 Würzburg/Allemagne (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 9 aut., 11 aut.); Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland/97074 Würzburg/Allemagne (6 aut.); Institute of Organic Chemistry, University of Würzburg, Am Hubland/97074 Würzburg/Allemagne (7 aut., 8 aut.); Institute of Virology and Immunology, University of Wurzburg, Versbacher Strasse 7/97078 Wurzburg/Allemagne (10 aut.) |
| DT : | Publication en série; Niveau analytique |
| SO : | Journal of medicinal chemistry : (Print); ISSN 0022-2623; Coden JMCMAR; Etats-Unis; Da. 2005; Vol. 48; No. 22; Pp. 6832-6842; Bibl. 63 ref. |
| LA : | Anglais |
| EA : | The coronavirus main protease, Mpro, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential Mpro inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed Mpro inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K1 value of 35.3 μM. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b. |
| CC : | 002B02S05 |
| FD : | Composé non peptide; Site actif; Inhibiteur enzyme; Virus syndrome respiratoire aigu sévère; Peptidases; Synthèse chimique; Modèle moléculaire; Modélisation; Prédiction; Relation structure activité; Antiviral; Inhibiteur protease; Complexe enzyme inhibiteur; Enone; Benzène dérivé; Carboxamide; Ether; In vitro; Mode liaison; Etacrynique acide amide |
| FG : | Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Chlore Composé organique |
| ED : | Non peptide compound; Active site; Enzyme inhibitor; Severe acute respiratory syndrome virus; Peptidases; Chemical synthesis; Molecular model; Modeling; Prediction; Structure activity relation; Antiviral; Protease inhibitor; Inhibitor enzyme complex; Enone; Benzene derivatives; Carboxamide; Ether; In vitro; Binding mode |
| EG : | Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Chlorine Organic compounds |
| SD : | Compuesto no péptido; Lugar activo; Inhibidor enzima; Severe acute respiratory syndrome virus; Peptidases; Síntesis química; Modelo molecular; Modelización; Predicción; Relación estructura actividad; Antiviral; Inhibidor proteasa; Complejo enzima inhibidor; Enona; Benceno derivado; Carboxamida; Eter; In vitro; Modo de enlace |
| LO : | INIST-9165.354000131970830110 |
| ID : | 06-0152074 |
Links to Exploration step
Pascal:06-0152074Le document en format XML
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first="John" last="Ziebuhr">John Ziebuhr</name><affiliation><inist:fA14 i1="04"><s1>Institute of Virology and Immunology, University of Wurzburg, Versbacher Strasse 7</s1><s2>97078 Wurzburg</s2><s3>DEU</s3><sZ>10 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Schirmeister, Tanja" sort="Schirmeister, Tanja" uniqKey="Schirmeister T" first="Tanja" last="Schirmeister">Tanja Schirmeister</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">06-0152074</idno><date when="2005">2005</date><idno type="stanalyst">PASCAL 06-0152074 INIST</idno><idno type="RBID">Pascal:06-0152074</idno><idno type="wicri:Area/PascalFrancis/Corpus">000538</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods</title><author><name sortKey="Kaeppler, Ulrich" sort="Kaeppler, Ulrich" uniqKey="Kaeppler U" first="Ulrich" last="Kaeppler">Ulrich Kaeppler</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Stiefl, Nikolaus" sort="Stiefl, Nikolaus" uniqKey="Stiefl N" first="Nikolaus" last="Stiefl">Nikolaus Stiefl</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Schiller, Markus" sort="Schiller, Markus" uniqKey="Schiller M" first="Markus" last="Schiller">Markus Schiller</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vicik, Radim" sort="Vicik, Radim" uniqKey="Vicik R" first="Radim" last="Vicik">Radim Vicik</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Breuning, Alexander" sort="Breuning, Alexander" uniqKey="Breuning A" first="Alexander" last="Breuning">Alexander Breuning</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Schmitz, Werner" sort="Schmitz, Werner" uniqKey="Schmitz W" first="Werner" last="Schmitz">Werner Schmitz</name><affiliation><inist:fA14 i1="02"><s1>Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>6 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Rupprecht, Daniel" sort="Rupprecht, Daniel" uniqKey="Rupprecht D" first="Daniel" last="Rupprecht">Daniel Rupprecht</name><affiliation><inist:fA14 i1="03"><s1>Institute of Organic Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Schmuck, Carsten" sort="Schmuck, Carsten" uniqKey="Schmuck C" first="Carsten" last="Schmuck">Carsten Schmuck</name><affiliation><inist:fA14 i1="03"><s1>Institute of Organic Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Baumann, Knut" sort="Baumann, Knut" uniqKey="Baumann K" first="Knut" last="Baumann">Knut Baumann</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name><affiliation><inist:fA14 i1="04"><s1>Institute of Virology and Immunology, University of Wurzburg, Versbacher Strasse 7</s1><s2>97078 Wurzburg</s2><s3>DEU</s3><sZ>10 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Schirmeister, Tanja" sort="Schirmeister, Tanja" uniqKey="Schirmeister T" first="Tanja" last="Schirmeister">Tanja Schirmeister</name><affiliation><inist:fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author></analytic><series><title level="j" type="main">Journal of medicinal chemistry : (Print)</title><title level="j" type="abbreviated">J. med. chem. : (Print)</title><idno type="ISSN">0022-2623</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title><title level="j" type="abbreviated">J. med. chem. : (Print)</title><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Active site</term><term>Antiviral</term><term>Benzene derivatives</term><term>Binding mode</term><term>Carboxamide</term><term>Chemical synthesis</term><term>Enone</term><term>Enzyme inhibitor</term><term>Ether</term><term>In vitro</term><term>Inhibitor enzyme complex</term><term>Modeling</term><term>Molecular model</term><term>Non peptide compound</term><term>Peptidases</term><term>Prediction</term><term>Protease inhibitor</term><term>Severe acute respiratory syndrome virus</term><term>Structure activity relation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Composé non peptide</term><term>Site actif</term><term>Inhibiteur enzyme</term><term>Virus syndrome respiratoire aigu sévère</term><term>Peptidases</term><term>Synthèse chimique</term><term>Modèle moléculaire</term><term>Modélisation</term><term>Prédiction</term><term>Relation structure activité</term><term>Antiviral</term><term>Inhibiteur protease</term><term>Complexe enzyme inhibiteur</term><term>Enone</term><term>Benzène dérivé</term><term>Carboxamide</term><term>Ether</term><term>In vitro</term><term>Mode liaison</term><term>Etacrynique acide amide</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The coronavirus main protease, M<sup>pro</sup>, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential M<sup>pro</sup> inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed M<sup>pro</sup> inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K<sub>1</sub> value of 35.3 μM. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0022-2623</s0></fA01><fA02 i1="01"><s0>JMCMAR</s0></fA02><fA03 i2="1"><s0>J. med. chem. : (Print)</s0></fA03><fA05><s2>48</s2></fA05><fA06><s2>22</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods</s1></fA08><fA11 i1="01" i2="1"><s1>KAEPPLER (Ulrich)</s1></fA11><fA11 i1="02" i2="1"><s1>STIEFL (Nikolaus)</s1></fA11><fA11 i1="03" i2="1"><s1>SCHILLER (Markus)</s1></fA11><fA11 i1="04" i2="1"><s1>VICIK (Radim)</s1></fA11><fA11 i1="05" i2="1"><s1>BREUNING (Alexander)</s1></fA11><fA11 i1="06" i2="1"><s1>SCHMITZ (Werner)</s1></fA11><fA11 i1="07" i2="1"><s1>RUPPRECHT (Daniel)</s1></fA11><fA11 i1="08" i2="1"><s1>SCHMUCK (Carsten)</s1></fA11><fA11 i1="09" i2="1"><s1>BAUMANN (Knut)</s1></fA11><fA11 i1="10" i2="1"><s1>ZIEBUHR (John)</s1></fA11><fA11 i1="11" i2="1"><s1>SCHIRMEISTER (Tanja)</s1></fA11><fA14 i1="01"><s1>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>6 aut.</sZ></fA14><fA14 i1="03"><s1>Institute of Organic Chemistry, University of Würzburg, Am Hubland</s1><s2>97074 Würzburg</s2><s3>DEU</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ></fA14><fA14 i1="04"><s1>Institute of Virology and Immunology, University of Wurzburg, Versbacher Strasse 7</s1><s2>97078 Wurzburg</s2><s3>DEU</s3><sZ>10 aut.</sZ></fA14><fA20><s1>6832-6842</s1></fA20><fA21><s1>2005</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>9165</s2><s5>354000131970830110</s5></fA43><fA44><s0>0000</s0><s1>© 2006 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>63 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>06-0152074</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Journal of medicinal chemistry : (Print)</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>The coronavirus main protease, M<sup>pro</sup>, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential M<sup>pro</sup> inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed M<sup>pro</sup> inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K<sub>1</sub> value of 35.3 μM. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02S05</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Composé non peptide</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Non peptide compound</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Compuesto no péptido</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Site actif</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Active site</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Lugar activo</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Enzyme inhibitor</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Inhibidor enzima</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Virus syndrome respiratoire aigu sévère</s0><s2>NW</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Severe acute respiratory syndrome virus</s0><s2>NW</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Severe acute respiratory syndrome virus</s0><s2>NW</s2><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Peptidases</s0><s2>FE</s2><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Peptidases</s0><s2>FE</s2><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Peptidases</s0><s2>FE</s2><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Synthèse chimique</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Chemical synthesis</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Síntesis química</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Modèle moléculaire</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Molecular model</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Modelo molecular</s0><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Modélisation</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Modeling</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Modelización</s0><s5>08</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Prédiction</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Prediction</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Predicción</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>Antiviral</s0><s5>11</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Antiviral</s0><s5>11</s5></fC03><fC03 i1="11" i2="X" l="SPA"><s0>Antiviral</s0><s5>11</s5></fC03><fC03 i1="12" i2="X" l="FRE"><s0>Inhibiteur protease</s0><s2>FR</s2><s5>12</s5></fC03><fC03 i1="12" i2="X" l="ENG"><s0>Protease inhibitor</s0><s2>FR</s2><s5>12</s5></fC03><fC03 i1="12" i2="X" l="SPA"><s0>Inhibidor proteasa</s0><s2>FR</s2><s5>12</s5></fC03><fC03 i1="13" i2="X" l="FRE"><s0>Complexe enzyme inhibiteur</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="ENG"><s0>Inhibitor enzyme complex</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="SPA"><s0>Complejo enzima inhibidor</s0><s5>13</s5></fC03><fC03 i1="14" i2="X" l="FRE"><s0>Enone</s0><s5>14</s5></fC03><fC03 i1="14" i2="X" l="ENG"><s0>Enone</s0><s5>14</s5></fC03><fC03 i1="14" i2="X" l="SPA"><s0>Enona</s0><s5>14</s5></fC03><fC03 i1="15" i2="X" l="FRE"><s0>Benzène dérivé</s0><s5>15</s5></fC03><fC03 i1="15" i2="X" l="ENG"><s0>Benzene derivatives</s0><s5>15</s5></fC03><fC03 i1="15" i2="X" l="SPA"><s0>Benceno derivado</s0><s5>15</s5></fC03><fC03 i1="16" i2="X" l="FRE"><s0>Carboxamide</s0><s5>17</s5></fC03><fC03 i1="16" i2="X" l="ENG"><s0>Carboxamide</s0><s5>17</s5></fC03><fC03 i1="16" i2="X" l="SPA"><s0>Carboxamida</s0><s5>17</s5></fC03><fC03 i1="17" i2="X" l="FRE"><s0>Ether</s0><s2>FX</s2><s5>18</s5></fC03><fC03 i1="17" i2="X" l="ENG"><s0>Ether</s0><s2>FX</s2><s5>18</s5></fC03><fC03 i1="17" i2="X" l="SPA"><s0>Eter</s0><s2>FX</s2><s5>18</s5></fC03><fC03 i1="18" i2="X" l="FRE"><s0>In vitro</s0><s5>19</s5></fC03><fC03 i1="18" i2="X" l="ENG"><s0>In vitro</s0><s5>19</s5></fC03><fC03 i1="18" i2="X" l="SPA"><s0>In vitro</s0><s5>19</s5></fC03><fC03 i1="19" i2="X" l="FRE"><s0>Mode liaison</s0><s5>20</s5></fC03><fC03 i1="19" i2="X" l="ENG"><s0>Binding mode</s0><s5>20</s5></fC03><fC03 i1="19" i2="X" l="SPA"><s0>Modo de enlace</s0><s5>20</s5></fC03><fC03 i1="20" i2="X" l="FRE"><s0>Etacrynique acide amide</s0><s2>NK</s2><s2>FR</s2><s4>INC</s4><s5>76</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Coronavirus</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Coronavirus</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Coronavirus</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Hydrolases</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><fC07 i1="07" i2="X" l="FRE"><s0>Chlore Composé organique</s0><s2>NC</s2><s2>FX</s2><s2>NA</s2><s5>16</s5></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Chlorine Organic compounds</s0><s2>NC</s2><s2>FX</s2><s2>NA</s2><s5>16</s5></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Cloro Compuesto orgánico</s0><s2>NC</s2><s2>FX</s2><s2>NA</s2><s5>16</s5></fC07><fN21><s1>093</s1></fN21></pA></standard><server><NO>PASCAL 06-0152074 INIST</NO><ET>A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods</ET><AU>KAEPPLER (Ulrich); STIEFL (Nikolaus); SCHILLER (Markus); VICIK (Radim); BREUNING (Alexander); SCHMITZ (Werner); RUPPRECHT (Daniel); SCHMUCK (Carsten); BAUMANN (Knut); ZIEBUHR (John); SCHIRMEISTER (Tanja)</AU><AF>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland/97074 Würzburg/Allemagne (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 9 aut., 11 aut.); Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland/97074 Würzburg/Allemagne (6 aut.); Institute of Organic Chemistry, University of Würzburg, Am Hubland/97074 Würzburg/Allemagne (7 aut., 8 aut.); Institute of Virology and Immunology, University of Wurzburg, Versbacher Strasse 7/97078 Wurzburg/Allemagne (10 aut.)</AF><DT>Publication en série; Niveau analytique</DT><SO>Journal of medicinal chemistry : (Print); ISSN 0022-2623; Coden JMCMAR; Etats-Unis; Da. 2005; Vol. 48; No. 22; Pp. 6832-6842; Bibl. 63 ref.</SO><LA>Anglais</LA><EA>The coronavirus main protease, M<sup>pro</sup>, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential M<sup>pro</sup> inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed M<sup>pro</sup> inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K<sub>1</sub> value of 35.3 μM. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.</EA><CC>002B02S05</CC><FD>Composé non peptide; Site actif; Inhibiteur enzyme; Virus syndrome respiratoire aigu sévère; Peptidases; Synthèse chimique; Modèle moléculaire; Modélisation; Prédiction; Relation structure activité; Antiviral; Inhibiteur protease; Complexe enzyme inhibiteur; Enone; Benzène dérivé; Carboxamide; Ether; In vitro; Mode liaison; Etacrynique acide amide</FD><FG>Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Chlore Composé organique</FG><ED>Non peptide compound; Active site; Enzyme inhibitor; Severe acute respiratory syndrome virus; Peptidases; Chemical synthesis; Molecular model; Modeling; Prediction; Structure activity relation; Antiviral; Protease inhibitor; Inhibitor enzyme complex; Enone; Benzene derivatives; Carboxamide; Ether; In vitro; Binding mode</ED><EG>Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Chlorine Organic compounds</EG><SD>Compuesto no péptido; Lugar activo; Inhibidor enzima; Severe acute respiratory syndrome virus; Peptidases; Síntesis química; Modelo molecular; Modelización; Predicción; Relación estructura actividad; Antiviral; Inhibidor proteasa; Complejo enzima inhibidor; Enona; Benceno derivado; Carboxamida; Eter; In vitro; Modo de enlace</SD><LO>INIST-9165.354000131970830110</LO><ID>06-0152074</ID></server></inist></record>Pour manipuler ce document sous Unix (Dilib)
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