Binding interaction of quercetin -3 -β -galactoside and its synthetic derivatives with SARS-CoV 3CLpro : Structure-activity relationship studies reveal salient pharmacophore features
Identifieur interne : 000391 ( PascalFrancis/Corpus ); précédent : 000390; suivant : 000392Binding interaction of quercetin -3 -β -galactoside and its synthetic derivatives with SARS-CoV 3CLpro : Structure-activity relationship studies reveal salient pharmacophore features
Auteurs : LILI CHEN ; JIAN LI ; CHENG LUO ; HONG LIU ; WEIJUN XU ; GANG CHEN ; OI WAH LIEW ; WEILIANG ZHU ; CHUM MOK PUAH ; XU SHEN ; HUALIANG JIANGSource :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2006.
Descripteurs français
- Pascal (Inist)
- Quercétine, Virus syndrome respiratoire aigu sévère, Relation structure activité, Modélisation, Peptidases, Syndrome respiratoire aigu sévère, Médicament, Cycle développement, Composé naturel, Inhibiteur protease, Modèle moléculaire, Prédiction, Spectrométrie fluorescence, Transfert énergie résonnant, Mutagenèse, Mutation, Structure secondaire, Fixation biologique, Synthèse chimique, Antiviral, Mécanisme action, Galactose, In vitro, Flavone dérivé, Polyphénol, Inhibiteur enzyme, Flavonoïde, Glycoside, Interaction moléculaire, Galactopyranoside dérivé, Criblage virtuel.
English descriptors
- KwdEn :
- Antiviral, Biological fixation, Chemical synthesis, Drug, Enzyme inhibitor, Flavone derivatives, Flavonoid, Fluorescence spectrometry, Galactose, Glycoside, In vitro, Life cycle, Mechanism of action, Modeling, Molecular interaction, Molecular model, Mutagenesis, Mutation, Natural compound, Peptidases, Polyphenol, Prediction, Protease inhibitor, Quercetin, Resonant energy transfer, Secondary structure, Severe acute respiratory syndrome, Severe acute respiratory syndrome virus, Structure activity relation, Virtual screening.
Abstract
The 3C-like protease (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-β-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Glnl89 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CLpro were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.
Notice en format standard (ISO 2709)
Pour connaître la documentation sur le format Inist Standard.
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Format Inist (serveur)
| NO : | PASCAL 07-0171458 INIST |
|---|---|
| ET : | Binding interaction of quercetin -3 -β -galactoside and its synthetic derivatives with SARS-CoV 3CLpro : Structure-activity relationship studies reveal salient pharmacophore features |
| AU : | LILI CHEN; JIAN LI; CHENG LUO; HONG LIU; WEIJUN XU; GANG CHEN; OI WAH LIEW; WEILIANG ZHU; CHUM MOK PUAH; XU SHEN; HUALIANG JIANG |
| AF : | Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences/Shanghai 201203/Chine (1 aut., 2 aut., 3 aut., 4 aut., 8 aut., 10 aut., 11 aut.); Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road/139651 Singapore/Singapour (5 aut., 6 aut., 7 aut., 9 aut.) |
| DT : | Publication en série; Niveau analytique |
| SO : | Bioorganic & medicinal chemistry; ISSN 0968-0896; Royaume-Uni; Da. 2006; Vol. 14; No. 24; Pp. 8295-8306 |
| LA : | Anglais |
| EA : | The 3C-like protease (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-β-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Glnl89 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CLpro were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme. |
| CC : | 002B02S05 |
| FD : | Quercétine; Virus syndrome respiratoire aigu sévère; Relation structure activité; Modélisation; Peptidases; Syndrome respiratoire aigu sévère; Médicament; Cycle développement; Composé naturel; Inhibiteur protease; Modèle moléculaire; Prédiction; Spectrométrie fluorescence; Transfert énergie résonnant; Mutagenèse; Mutation; Structure secondaire; Fixation biologique; Synthèse chimique; Antiviral; Mécanisme action; Galactose; In vitro; Flavone dérivé; Polyphénol; Inhibiteur enzyme; Flavonoïde; Glycoside; Interaction moléculaire; Galactopyranoside dérivé; Criblage virtuel |
| FG : | Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Virose; Infection; Appareil respiratoire pathologie; Poumon pathologie |
| ED : | Quercetin; Severe acute respiratory syndrome virus; Structure activity relation; Modeling; Peptidases; Severe acute respiratory syndrome; Drug; Life cycle; Natural compound; Protease inhibitor; Molecular model; Prediction; Fluorescence spectrometry; Resonant energy transfer; Mutagenesis; Mutation; Secondary structure; Biological fixation; Chemical synthesis; Antiviral; Mechanism of action; Galactose; In vitro; Flavone derivatives; Polyphenol; Enzyme inhibitor; Flavonoid; Glycoside; Molecular interaction; Virtual screening |
| EG : | Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Viral disease; Infection; Respiratory disease; Lung disease |
| SD : | Quercetina; Severe acute respiratory syndrome virus; Relación estructura actividad; Modelización; Peptidases; Síndrome respiratorio agudo severo; Medicamento; Ciclo desarrollo; Compuesto natural; Inhibidor proteasa; Modelo molecular; Predicción; Espectrometría fluorescencia; Transferencia energía resonante; Mutagénesis; Mutación; Estructura secundaria; Fijación biológica; Síntesis química; Antiviral; Mecanismo acción; Galactosa; In vitro; Flavona derivado; Polifenol; Inhibidor enzima; Flavonoide; Glicósido; Interacción molecular; Cribado virtual |
| LO : | INIST-26564.354000158983650130 |
| ID : | 07-0171458 |
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Pascal:07-0171458Le document en format XML
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aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Weiliang Zhu" sort="Weiliang Zhu" uniqKey="Weiliang Zhu" last="Weiliang Zhu">WEILIANG ZHU</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Chum Mok Puah" sort="Chum Mok Puah" uniqKey="Chum Mok Puah" last="Chum Mok Puah">CHUM MOK PUAH</name><affiliation><inist:fA14 i1="02"><s1>Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road</s1><s2>139651 Singapore</s2><s3>SGP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Xu Shen" sort="Xu Shen" uniqKey="Xu Shen" last="Xu Shen">XU SHEN</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Hualiang Jiang" sort="Hualiang Jiang" uniqKey="Hualiang Jiang" last="Hualiang Jiang">HUALIANG JIANG</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">07-0171458</idno><date when="2006">2006</date><idno type="stanalyst">PASCAL 07-0171458 INIST</idno><idno type="RBID">Pascal:07-0171458</idno><idno type="wicri:Area/PascalFrancis/Corpus">000391</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Binding interaction of quercetin -3 -β -galactoside and its synthetic derivatives with SARS-CoV 3CL<sup>pro</sup> : Structure-activity relationship studies reveal salient pharmacophore features</title><author><name sortKey="Lili Chen" sort="Lili Chen" uniqKey="Lili Chen" last="Lili Chen">LILI CHEN</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Jian Li" sort="Jian Li" uniqKey="Jian Li" last="Jian Li">JIAN LI</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Cheng Luo" sort="Cheng Luo" uniqKey="Cheng Luo" last="Cheng Luo">CHENG LUO</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Hong Liu" sort="Hong Liu" uniqKey="Hong Liu" last="Hong Liu">HONG LIU</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Weijun Xu" sort="Weijun Xu" uniqKey="Weijun Xu" last="Weijun Xu">WEIJUN XU</name><affiliation><inist:fA14 i1="02"><s1>Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road</s1><s2>139651 Singapore</s2><s3>SGP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Gang Chen" sort="Gang Chen" uniqKey="Gang Chen" last="Gang Chen">GANG CHEN</name><affiliation><inist:fA14 i1="02"><s1>Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road</s1><s2>139651 Singapore</s2><s3>SGP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Oi Wah Liew" sort="Oi Wah Liew" uniqKey="Oi Wah Liew" last="Oi Wah Liew">OI WAH LIEW</name><affiliation><inist:fA14 i1="02"><s1>Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road</s1><s2>139651 Singapore</s2><s3>SGP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Weiliang Zhu" sort="Weiliang Zhu" uniqKey="Weiliang Zhu" last="Weiliang Zhu">WEILIANG ZHU</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Chum Mok Puah" sort="Chum Mok Puah" uniqKey="Chum Mok Puah" last="Chum Mok Puah">CHUM MOK PUAH</name><affiliation><inist:fA14 i1="02"><s1>Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road</s1><s2>139651 Singapore</s2><s3>SGP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Xu Shen" sort="Xu Shen" uniqKey="Xu Shen" last="Xu Shen">XU SHEN</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Hualiang Jiang" sort="Hualiang Jiang" uniqKey="Hualiang Jiang" last="Hualiang Jiang">HUALIANG JIANG</name><affiliation><inist:fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14></affiliation></author></analytic><series><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Biological fixation</term><term>Chemical synthesis</term><term>Drug</term><term>Enzyme inhibitor</term><term>Flavone derivatives</term><term>Flavonoid</term><term>Fluorescence spectrometry</term><term>Galactose</term><term>Glycoside</term><term>In vitro</term><term>Life cycle</term><term>Mechanism of action</term><term>Modeling</term><term>Molecular interaction</term><term>Molecular model</term><term>Mutagenesis</term><term>Mutation</term><term>Natural compound</term><term>Peptidases</term><term>Polyphenol</term><term>Prediction</term><term>Protease inhibitor</term><term>Quercetin</term><term>Resonant energy transfer</term><term>Secondary structure</term><term>Severe acute respiratory syndrome</term><term>Severe acute respiratory syndrome virus</term><term>Structure activity relation</term><term>Virtual screening</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Quercétine</term><term>Virus syndrome respiratoire aigu sévère</term><term>Relation structure activité</term><term>Modélisation</term><term>Peptidases</term><term>Syndrome respiratoire aigu sévère</term><term>Médicament</term><term>Cycle développement</term><term>Composé naturel</term><term>Inhibiteur protease</term><term>Modèle moléculaire</term><term>Prédiction</term><term>Spectrométrie fluorescence</term><term>Transfert énergie résonnant</term><term>Mutagenèse</term><term>Mutation</term><term>Structure secondaire</term><term>Fixation biologique</term><term>Synthèse chimique</term><term>Antiviral</term><term>Mécanisme action</term><term>Galactose</term><term>In vitro</term><term>Flavone dérivé</term><term>Polyphénol</term><term>Inhibiteur enzyme</term><term>Flavonoïde</term><term>Glycoside</term><term>Interaction moléculaire</term><term>Galactopyranoside dérivé</term><term>Criblage virtuel</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The 3C-like protease (3CL<sup>pro</sup>) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-β-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Glnl89 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CL<sup>pro</sup> were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0968-0896</s0></fA01><fA03 i2="1"><s0>Bioorg. med. chem.</s0></fA03><fA05><s2>14</s2></fA05><fA06><s2>24</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Binding interaction of quercetin -3 -β -galactoside and its synthetic derivatives with SARS-CoV 3CL<sup>pro</sup> : Structure-activity relationship studies reveal salient pharmacophore features</s1></fA08><fA11 i1="01" i2="1"><s1>LILI CHEN</s1></fA11><fA11 i1="02" i2="1"><s1>JIAN LI</s1></fA11><fA11 i1="03" i2="1"><s1>CHENG LUO</s1></fA11><fA11 i1="04" i2="1"><s1>HONG LIU</s1></fA11><fA11 i1="05" i2="1"><s1>WEIJUN XU</s1></fA11><fA11 i1="06" i2="1"><s1>GANG CHEN</s1></fA11><fA11 i1="07" i2="1"><s1>OI WAH LIEW</s1></fA11><fA11 i1="08" i2="1"><s1>WEILIANG ZHU</s1></fA11><fA11 i1="09" i2="1"><s1>CHUM MOK PUAH</s1></fA11><fA11 i1="10" i2="1"><s1>XU SHEN</s1></fA11><fA11 i1="11" i2="1"><s1>HUALIANG JIANG</s1></fA11><fA14 i1="01"><s1>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></fA14><fA14 i1="02"><s1>Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road</s1><s2>139651 Singapore</s2><s3>SGP</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></fA14><fA20><s1>8295-8306</s1></fA20><fA21><s1>2006</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>26564</s2><s5>354000158983650130</s5></fA43><fA44><s0>0000</s0><s1>© 2007 INIST-CNRS. All rights reserved.</s1></fA44><fA47 i1="01" i2="1"><s0>07-0171458</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Bioorganic & medicinal chemistry</s0></fA64><fA66 i1="01"><s0>GBR</s0></fA66><fA99><s0>1 p.1/4 ref. et notes</s0></fA99><fC01 i1="01" l="ENG"><s0>The 3C-like protease (3CL<sup>pro</sup>) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-β-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Glnl89 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CL<sup>pro</sup> were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02S05</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Quercétine</s0><s2>NK</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Quercetin</s0><s2>NK</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Quercetina</s0><s2>NK</s2><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Virus syndrome respiratoire aigu sévère</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Severe acute respiratory syndrome virus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Severe acute respiratory syndrome virus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Relation structure activité</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Structure activity relation</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Relación estructura actividad</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Modélisation</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Modeling</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Modelización</s0><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>Syndrome respiratoire aigu sévère</s0><s2>NM</s2><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Severe acute respiratory syndrome</s0><s2>NM</s2><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Síndrome respiratorio agudo severo</s0><s2>NM</s2><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Médicament</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Drug</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Medicamento</s0><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Cycle développement</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Life cycle</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Ciclo desarrollo</s0><s5>08</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Composé naturel</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Natural compound</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Compuesto natural</s0><s5>09</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Inhibiteur protease</s0><s2>FR</s2><s5>10</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Protease inhibitor</s0><s2>FR</s2><s5>10</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Inhibidor proteasa</s0><s2>FR</s2><s5>10</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Modèle moléculaire</s0><s5>11</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Molecular model</s0><s5>11</s5></fC03><fC03 i1="11" i2="X" l="SPA"><s0>Modelo molecular</s0><s5>11</s5></fC03><fC03 i1="12" i2="X" l="FRE"><s0>Prédiction</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="ENG"><s0>Prediction</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="SPA"><s0>Predicción</s0><s5>12</s5></fC03><fC03 i1="13" i2="X" l="FRE"><s0>Spectrométrie fluorescence</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="ENG"><s0>Fluorescence spectrometry</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="SPA"><s0>Espectrometría fluorescencia</s0><s5>13</s5></fC03><fC03 i1="14" i2="X" l="FRE"><s0>Transfert énergie résonnant</s0><s5>14</s5></fC03><fC03 i1="14" i2="X" l="ENG"><s0>Resonant energy transfer</s0><s5>14</s5></fC03><fC03 i1="14" i2="X" l="SPA"><s0>Transferencia energía resonante</s0><s5>14</s5></fC03><fC03 i1="15" i2="X" l="FRE"><s0>Mutagenèse</s0><s5>15</s5></fC03><fC03 i1="15" i2="X" l="ENG"><s0>Mutagenesis</s0><s5>15</s5></fC03><fC03 i1="15" i2="X" l="SPA"><s0>Mutagénesis</s0><s5>15</s5></fC03><fC03 i1="16" i2="X" l="FRE"><s0>Mutation</s0><s5>16</s5></fC03><fC03 i1="16" i2="X" l="ENG"><s0>Mutation</s0><s5>16</s5></fC03><fC03 i1="16" i2="X" 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l="SPA"><s0>Polifenol</s0><s5>33</s5></fC03><fC03 i1="26" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0><s5>34</s5></fC03><fC03 i1="26" i2="X" l="ENG"><s0>Enzyme inhibitor</s0><s5>34</s5></fC03><fC03 i1="26" i2="X" l="SPA"><s0>Inhibidor enzima</s0><s5>34</s5></fC03><fC03 i1="27" i2="X" l="FRE"><s0>Flavonoïde</s0><s5>35</s5></fC03><fC03 i1="27" i2="X" l="ENG"><s0>Flavonoid</s0><s5>35</s5></fC03><fC03 i1="27" i2="X" l="SPA"><s0>Flavonoide</s0><s5>35</s5></fC03><fC03 i1="28" i2="X" l="FRE"><s0>Glycoside</s0><s5>36</s5></fC03><fC03 i1="28" i2="X" l="ENG"><s0>Glycoside</s0><s5>36</s5></fC03><fC03 i1="28" i2="X" l="SPA"><s0>Glicósido</s0><s5>36</s5></fC03><fC03 i1="29" i2="X" l="FRE"><s0>Interaction moléculaire</s0><s5>37</s5></fC03><fC03 i1="29" i2="X" l="ENG"><s0>Molecular interaction</s0><s5>37</s5></fC03><fC03 i1="29" i2="X" l="SPA"><s0>Interacción molecular</s0><s5>37</s5></fC03><fC03 i1="30" i2="X" l="FRE"><s0>Galactopyranoside dérivé</s0><s2>NK</s2><s4>INC</s4><s5>76</s5></fC03><fC03 i1="31" i2="X" l="FRE"><s0>Criblage virtuel</s0><s4>CD</s4><s5>96</s5></fC03><fC03 i1="31" i2="X" l="ENG"><s0>Virtual screening</s0><s4>CD</s4><s5>96</s5></fC03><fC03 i1="31" i2="X" l="SPA"><s0>Cribado virtual</s0><s4>CD</s4><s5>96</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>Virose</s0></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Viral disease</s0></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Virosis</s0></fC07><fC07 i1="08" i2="X" l="FRE"><s0>Infection</s0></fC07><fC07 i1="08" i2="X" l="ENG"><s0>Infection</s0></fC07><fC07 i1="08" i2="X" l="SPA"><s0>Infección</s0></fC07><fC07 i1="09" i2="X" l="FRE"><s0>Appareil respiratoire pathologie</s0><s5>53</s5></fC07><fC07 i1="09" i2="X" l="ENG"><s0>Respiratory disease</s0><s5>53</s5></fC07><fC07 i1="09" i2="X" l="SPA"><s0>Aparato respiratorio patología</s0><s5>53</s5></fC07><fC07 i1="10" i2="X" l="FRE"><s0>Poumon pathologie</s0><s5>54</s5></fC07><fC07 i1="10" i2="X" l="ENG"><s0>Lung disease</s0><s5>54</s5></fC07><fC07 i1="10" i2="X" l="SPA"><s0>Pulmón patología</s0><s5>54</s5></fC07><fN21><s1>121</s1></fN21></pA></standard><server><NO>PASCAL 07-0171458 INIST</NO><ET>Binding interaction of quercetin -3 -β -galactoside and its synthetic derivatives with SARS-CoV 3CL<sup>pro</sup> : Structure-activity relationship studies reveal salient pharmacophore features</ET><AU>LILI CHEN; JIAN LI; CHENG LUO; HONG LIU; WEIJUN XU; GANG CHEN; OI WAH LIEW; WEILIANG ZHU; CHUM MOK PUAH; XU SHEN; HUALIANG JIANG</AU><AF>Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences/Shanghai 201203/Chine (1 aut., 2 aut., 3 aut., 4 aut., 8 aut., 10 aut., 11 aut.); Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road/139651 Singapore/Singapour (5 aut., 6 aut., 7 aut., 9 aut.)</AF><DT>Publication en série; Niveau analytique</DT><SO>Bioorganic & medicinal chemistry; ISSN 0968-0896; Royaume-Uni; Da. 2006; Vol. 14; No. 24; Pp. 8295-8306</SO><LA>Anglais</LA><EA>The 3C-like protease (3CL<sup>pro</sup>) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-β-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Glnl89 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CL<sup>pro</sup> were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.</EA><CC>002B02S05</CC><FD>Quercétine; Virus syndrome respiratoire aigu sévère; Relation structure activité; Modélisation; Peptidases; Syndrome respiratoire aigu sévère; Médicament; Cycle développement; Composé naturel; Inhibiteur protease; Modèle moléculaire; Prédiction; Spectrométrie fluorescence; Transfert énergie résonnant; Mutagenèse; Mutation; Structure secondaire; Fixation biologique; Synthèse chimique; Antiviral; Mécanisme action; Galactose; In vitro; Flavone dérivé; Polyphénol; Inhibiteur enzyme; Flavonoïde; Glycoside; Interaction moléculaire; Galactopyranoside dérivé; Criblage virtuel</FD><FG>Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Virose; Infection; Appareil respiratoire pathologie; Poumon pathologie</FG><ED>Quercetin; Severe acute respiratory syndrome virus; Structure activity relation; Modeling; Peptidases; Severe acute respiratory syndrome; Drug; Life cycle; Natural compound; Protease inhibitor; Molecular model; Prediction; Fluorescence spectrometry; Resonant energy transfer; Mutagenesis; Mutation; Secondary structure; Biological fixation; Chemical synthesis; Antiviral; Mechanism of action; Galactose; In vitro; Flavone derivatives; Polyphenol; Enzyme inhibitor; Flavonoid; Glycoside; Molecular interaction; Virtual screening</ED><EG>Coronavirus; Coronaviridae; Nidovirales; Virus; Hydrolases; Enzyme; Viral disease; Infection; Respiratory disease; Lung disease</EG><SD>Quercetina; Severe acute respiratory syndrome virus; Relación estructura actividad; Modelización; Peptidases; Síndrome respiratorio agudo severo; Medicamento; Ciclo desarrollo; Compuesto natural; Inhibidor proteasa; Modelo molecular; Predicción; Espectrometría fluorescencia; Transferencia energía resonante; Mutagénesis; Mutación; Estructura secundaria; Fijación biológica; Síntesis química; Antiviral; Mecanismo acción; Galactosa; In vitro; Flavona derivado; Polifenol; Inhibidor enzima; Flavonoide; Glicósido; Interacción molecular; Cribado virtual</SD><LO>INIST-26564.354000158983650130</LO><ID>07-0171458</ID></server></inist></record>Pour manipuler ce document sous Unix (Dilib)
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