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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 : 000723

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

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 :

RBID : Pascal:06-0152074

Descripteurs français

English descriptors

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.


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Pascal:06-0152074

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<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>
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<term>Peptidases</term>
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<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>
</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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   |wiki=    Sante
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