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 : 004A17 ( Main/Exploration ); précédent : 004A16; suivant : 004A18A 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 [ 0022-2623 ] ; 2005.
Descripteurs français
- KwdFr :
- Acide étacrynique (), Acide étacrynique (analogues et dérivés), Acide étacrynique (synthèse chimique), Amides (), Amides (pharmacologie), Amides (synthèse chimique), Chromatographie en phase liquide à haute performance, Cysteine endopeptidases, Endopeptidases (), Inhibiteurs de protéases (), Inhibiteurs de protéases (synthèse chimique), Modèles moléculaires, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Relation structure-activité, Sites de fixation, Virus du SRAS (enzymologie).
- MESH :
- analogues et dérivés : Acide étacrynique.
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- pharmacologie : Amides.
- synthèse chimique : Acide étacrynique, Amides, Inhibiteurs de protéases.
- Acide étacrynique, Amides, Chromatographie en phase liquide à haute performance, Cysteine endopeptidases, Endopeptidases, Inhibiteurs de protéases, Modèles moléculaires, Protéines virales, Relation structure-activité, Sites de fixation.
- Pascal (Inist)
- Antiviral, Benzène dérivé, Carboxamide, Complexe enzyme inhibiteur, Composé non peptide, Enone, Etacrynique acide amide, Ether, In vitro, Inhibiteur enzyme, Inhibiteur protease, Mode liaison, Modèle moléculaire, Modélisation, Peptidases, Prédiction, Relation structure activité, Site actif, Synthèse chimique, Virus syndrome respiratoire aigu sévère.
English descriptors
- KwdEn :
- Active site, Amides (chemical synthesis), Amides (chemistry), Amides (pharmacology), Antiviral, Benzene derivatives, Binding Sites, Binding mode, Carboxamide, Chemical synthesis, Chromatography, High Pressure Liquid, Cysteine Endopeptidases, Endopeptidases (chemistry), Enone, Enzyme inhibitor, Ethacrynic Acid (analogs & derivatives), Ethacrynic Acid (chemical synthesis), Ethacrynic Acid (chemistry), Ether, In vitro, Inhibitor enzyme complex, Modeling, Models, Molecular, Molecular model, Non peptide compound, Peptidases, Prediction, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease inhibitor, SARS Virus (enzymology), Severe acute respiratory syndrome virus, Structure activity relation, Structure-Activity Relationship, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
- MESH :
- chemical , analogs & derivatives : Ethacrynic Acid.
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Amides, Ethacrynic Acid, Protease Inhibitors.
- chemical , chemistry : Amides, Endopeptidases, Ethacrynic Acid, Protease Inhibitors, Viral Proteins.
- chemical , pharmacology : Amides.
- enzymology : SARS Virus.
- Binding Sites, Chromatography, High Pressure Liquid, Cysteine Endopeptidases, Models, Molecular, Structure-Activity Relationship.
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 Ki 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.
Url:
DOI: 10.1021/jm0501782
Affiliations:
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Le document en format XML
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type="city">Wurtzbourg</settlement></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Stiefl, Nikolaus" sort="Stiefl, Nikolaus" uniqKey="Stiefl N" first="Nikolaus" last="Stiefl">Nikolaus Stiefl</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany,Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, D-97074 Würzburg,Germany, Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, andInstitute of Virology and Immunology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Schiller, Markus" sort="Schiller, Markus" uniqKey="Schiller M" first="Markus" last="Schiller">Markus Schiller</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany,Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, D-97074 Würzburg,Germany, Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, andInstitute of Virology and Immunology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement 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type="city">Wurtzbourg</settlement></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Schmitz, Werner" sort="Schmitz, Werner" uniqKey="Schmitz W" first="Werner" last="Schmitz">Werner Schmitz</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany,Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, D-97074 Würzburg,Germany, Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, andInstitute of Virology and Immunology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement 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type="city">Wurtzbourg</settlement></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Baumann, Knut" sort="Baumann, Knut" uniqKey="Baumann K" first="Knut" last="Baumann">Knut Baumann</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany,Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, D-97074 Würzburg,Germany, Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, andInstitute of Virology and Immunology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany,Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, D-97074 Würzburg,Germany, Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, andInstitute of Virology and Immunology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation><affiliation></affiliation></author><author><name sortKey="Schirmeister, Tanja" sort="Schirmeister, Tanja" uniqKey="Schirmeister T" first="Tanja" last="Schirmeister">Tanja Schirmeister</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany,Department of Physiological Chemistry II, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, D-97074 Würzburg,Germany, Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, andInstitute of Virology and Immunology, University of Würzburg, Versbacher Strasse 7, D-97078 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Allemagne</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Medicinal Chemistry</title><title level="j" type="abbrev">J. Med. Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2005</date><date type="published">2005</date><biblScope unit="vol">48</biblScope><biblScope unit="issue">22</biblScope><biblScope unit="page" from="6832">6832</biblScope><biblScope unit="page" to="6842">6842</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Active site</term><term>Amides (chemical synthesis)</term><term>Amides (chemistry)</term><term>Amides (pharmacology)</term><term>Antiviral</term><term>Benzene derivatives</term><term>Binding Sites</term><term>Binding mode</term><term>Carboxamide</term><term>Chemical synthesis</term><term>Chromatography, High Pressure Liquid</term><term>Cysteine Endopeptidases</term><term>Endopeptidases (chemistry)</term><term>Enone</term><term>Enzyme inhibitor</term><term>Ethacrynic Acid (analogs & derivatives)</term><term>Ethacrynic Acid (chemical synthesis)</term><term>Ethacrynic Acid (chemistry)</term><term>Ether</term><term>In vitro</term><term>Inhibitor enzyme complex</term><term>Modeling</term><term>Models, Molecular</term><term>Molecular model</term><term>Non peptide compound</term><term>Peptidases</term><term>Prediction</term><term>Protease Inhibitors (chemical synthesis)</term><term>Protease Inhibitors (chemistry)</term><term>Protease inhibitor</term><term>SARS Virus (enzymology)</term><term>Severe acute respiratory syndrome virus</term><term>Structure activity relation</term><term>Structure-Activity Relationship</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acide étacrynique ()</term><term>Acide étacrynique (analogues et dérivés)</term><term>Acide étacrynique (synthèse chimique)</term><term>Amides ()</term><term>Amides (pharmacologie)</term><term>Amides (synthèse chimique)</term><term>Chromatographie en phase liquide à haute performance</term><term>Cysteine endopeptidases</term><term>Endopeptidases ()</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (synthèse chimique)</term><term>Modèles moléculaires</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Relation structure-activité</term><term>Sites de fixation</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Ethacrynic Acid</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Amides</term><term>Ethacrynic Acid</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amides</term><term>Endopeptidases</term><term>Ethacrynic Acid</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Amides</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Acide étacrynique</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Amides</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Acide étacrynique</term><term>Amides</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Chromatography, High Pressure Liquid</term><term>Cysteine Endopeptidases</term><term>Models, Molecular</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acide étacrynique</term><term>Amides</term><term>Chromatographie en phase liquide à haute performance</term><term>Cysteine endopeptidases</term><term>Endopeptidases</term><term>Inhibiteurs de protéases</term><term>Modèles moléculaires</term><term>Protéines virales</term><term>Relation structure-activité</term><term>Sites de fixation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Antiviral</term><term>Benzène dérivé</term><term>Carboxamide</term><term>Complexe enzyme inhibiteur</term><term>Composé non peptide</term><term>Enone</term><term>Etacrynique acide amide</term><term>Ether</term><term>In vitro</term><term>Inhibiteur enzyme</term><term>Inhibiteur protease</term><term>Mode liaison</term><term>Modèle moléculaire</term><term>Modélisation</term><term>Peptidases</term><term>Prédiction</term><term>Relation structure activité</term><term>Site actif</term><term>Synthèse chimique</term><term>Virus syndrome respiratoire aigu sévère</term></keywords></textClass></profileDesc></teiHeader><front><div type="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 Ki 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><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="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>Pour manipuler ce document sous Unix (Dilib)
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