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 : 000722 ( PascalFrancis/Checkpoint ); précédent : 000721; suivant : 000723A 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 [Allemagne] ; Nikolaus Stiefl [Allemagne] ; Markus Schiller [Allemagne] ; Radim Vicik [Allemagne] ; Alexander Breuning [Allemagne] ; Werner Schmitz [Allemagne] ; Daniel Rupprecht [Allemagne] ; Carsten Schmuck [Allemagne] ; Knut Baumann [Allemagne] ; John Ziebuhr [Allemagne] ; Tanja Schirmeister [Allemagne]Source :
- 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.
Affiliations:
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Pascal:06-0152074Le document en format XML
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<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>
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<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>
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<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>
</inist>
<affiliations><list><country><li>Allemagne</li>
</country>
<region><li>Bavière</li>
<li>District de Basse-Franconie</li>
</region>
<settlement><li>Wurtzbourg</li>
</settlement>
</list>
<tree><country name="Allemagne"><region name="Bavière"><name sortKey="Kaeppler, Ulrich" sort="Kaeppler, Ulrich" uniqKey="Kaeppler U" first="Ulrich" last="Kaeppler">Ulrich Kaeppler</name>
</region>
<name sortKey="Baumann, Knut" sort="Baumann, Knut" uniqKey="Baumann K" first="Knut" last="Baumann">Knut Baumann</name>
<name sortKey="Breuning, Alexander" sort="Breuning, Alexander" uniqKey="Breuning A" first="Alexander" last="Breuning">Alexander Breuning</name>
<name sortKey="Rupprecht, Daniel" sort="Rupprecht, Daniel" uniqKey="Rupprecht D" first="Daniel" last="Rupprecht">Daniel Rupprecht</name>
<name sortKey="Schiller, Markus" sort="Schiller, Markus" uniqKey="Schiller M" first="Markus" last="Schiller">Markus Schiller</name>
<name sortKey="Schirmeister, Tanja" sort="Schirmeister, Tanja" uniqKey="Schirmeister T" first="Tanja" last="Schirmeister">Tanja Schirmeister</name>
<name sortKey="Schmitz, Werner" sort="Schmitz, Werner" uniqKey="Schmitz W" first="Werner" last="Schmitz">Werner Schmitz</name>
<name sortKey="Schmuck, Carsten" sort="Schmuck, Carsten" uniqKey="Schmuck C" first="Carsten" last="Schmuck">Carsten Schmuck</name>
<name sortKey="Stiefl, Nikolaus" sort="Stiefl, Nikolaus" uniqKey="Stiefl N" first="Nikolaus" last="Stiefl">Nikolaus Stiefl</name>
<name sortKey="Vicik, Radim" sort="Vicik, Radim" uniqKey="Vicik R" first="Radim" last="Vicik">Radim Vicik</name>
<name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name>
</country>
</tree>
</affiliations>
</record>
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