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 : 001230 ( Ncbi/Checkpoint ); précédent : 001229; suivant : 001231A 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 ; Markus Schiller ; Radim Vicik ; Alexander Breuning ; Werner Schmitz ; Daniel Rupprecht ; Carsten Schmuck ; Knut Baumann ; John Ziebuhr ; Tanja SchirmeisterSource :
- 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.
English descriptors
- KwdEn :
- Amides (chemical synthesis), Amides (chemistry), Amides (pharmacology), Binding Sites, Chromatography, High Pressure Liquid, Cysteine Endopeptidases, Endopeptidases (chemistry), Ethacrynic Acid (analogs & derivatives), Ethacrynic Acid (chemical synthesis), Ethacrynic Acid (chemistry), Models, Molecular, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), SARS Virus (enzymology), 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, M(pro), 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(pro) 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(pro) inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K(i) value of 35.3 muM. 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.
DOI: 10.1021/jm0501782
PubMed: 16250642
Affiliations:
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D" first="Daniel" last="Rupprecht">Daniel Rupprecht</name></author><author><name sortKey="Schmuck, Carsten" sort="Schmuck, Carsten" uniqKey="Schmuck C" first="Carsten" last="Schmuck">Carsten Schmuck</name></author><author><name sortKey="Baumann, Knut" sort="Baumann, Knut" uniqKey="Baumann K" first="Knut" last="Baumann">Knut Baumann</name></author><author><name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name></author><author><name sortKey="Schirmeister, Tanja" sort="Schirmeister, Tanja" uniqKey="Schirmeister T" first="Tanja" last="Schirmeister">Tanja Schirmeister</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="ISSN">0022-2623</idno><imprint><date when="2005" type="published">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amides (chemical synthesis)</term><term>Amides (chemistry)</term><term>Amides (pharmacology)</term><term>Binding Sites</term><term>Chromatography, High Pressure Liquid</term><term>Cysteine Endopeptidases</term><term>Endopeptidases (chemistry)</term><term>Ethacrynic Acid (analogs & derivatives)</term><term>Ethacrynic Acid (chemical synthesis)</term><term>Ethacrynic Acid (chemistry)</term><term>Models, Molecular</term><term>Protease Inhibitors (chemical synthesis)</term><term>Protease Inhibitors (chemistry)</term><term>SARS Virus (enzymology)</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 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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></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The coronavirus main protease, M(pro), 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(pro) 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(pro) inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K(i) value of 35.3 muM. 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><noCountry><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></noCountry><country name="Allemagne"><region name="Bavière"><name sortKey="Kaeppler, Ulrich" sort="Kaeppler, Ulrich" uniqKey="Kaeppler U" first="Ulrich" last="Kaeppler">Ulrich Kaeppler</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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