Molecular modeling and chemical modification for finding peptide inhibitor against severe acute respiratory syndrome coronavirus main proteinase.
Identifieur interne : 004751 ( Main/Exploration ); précédent : 004750; suivant : 004752Molecular modeling and chemical modification for finding peptide inhibitor against severe acute respiratory syndrome coronavirus main proteinase.
Auteurs : Qishi Du [République populaire de Chine] ; Shuqing Wang ; Dongqing Wei ; Suzanne Sirois ; Kuo-Chen ChouSource :
- Analytical biochemistry [ 0003-2697 ] ; 2005.
Descripteurs français
- KwdFr :
- Antienzymes (), Antienzymes (isolement et purification), Antienzymes (pharmacologie), Interactions hydrophobes et hydrophiles, Maladie aigüe, Modèles moléculaires, Peptide hydrolases (métabolisme), Structure moléculaire, Structure tertiaire des protéines, Syndrome respiratoire aigu sévère (traitement médicamenteux), Syndrome respiratoire aigu sévère (virologie), Théorie quantique, Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Virus du SRAS.
- isolement et purification : Antienzymes.
- métabolisme : Peptide hydrolases.
- pharmacologie : Antienzymes.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- virologie : Syndrome respiratoire aigu sévère.
- Antienzymes, Interactions hydrophobes et hydrophiles, Maladie aigüe, Modèles moléculaires, Structure moléculaire, Structure tertiaire des protéines, Théorie quantique, Virus du SRAS.
English descriptors
- KwdEn :
- Acute Disease, Enzyme Inhibitors (chemistry), Enzyme Inhibitors (isolation & purification), Enzyme Inhibitors (pharmacology), Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Structure, Peptide Hydrolases (metabolism), Protein Structure, Tertiary, Quantum Theory, SARS Virus (drug effects), SARS Virus (enzymology), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (virology).
- MESH :
- chemical , chemistry : Enzyme Inhibitors.
- chemical , isolation & purification : Enzyme Inhibitors.
- chemical , metabolism : Peptide Hydrolases.
- chemical , pharmacology : Enzyme Inhibitors.
- drug effects : SARS Virus.
- drug therapy : Severe Acute Respiratory Syndrome.
- enzymology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Acute Disease, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Structure, Protein Structure, Tertiary, Quantum Theory.
Abstract
Severe acute respiratory syndrome (SARS) is a respiratory disease caused by a newly found virus, called SARS coronavirus. In this study, the cleavage mechanism of the SARS coronavirus main proteinase (Mpro or 3CLpro) on the octapeptide NH2-AVLQ downward arrowSGFR-COOH was investigated using molecular mechanics and quantum mechanics simulations based on the experimental structure of the proteinase. It has been observed that the catalytic dyad (His-41/Cys-145) site between domains I and II attracts the pi electron density from the peptide bond Gln-Ser, increasing the positive charge on C(CO) of Gln and the negative charge on N(NH) of Ser, so as to weaken the Gln-Ser peptide bond. The catalytic functional group is the imidazole group of His-41 and the S in Cys-145. Ndelta1 on the imidazole ring plays the acid-base catalytic role. Based on the "distorted key theory" [K.C. Chou, Anal. Biochem. 233 (1996) 1-14], the possibility to convert the octapeptide to a competent inhibitor has been studied. It has been found that the chemical bond between Gln and Ser will become much stronger and no longer cleavable by the SARS enzyme after either changing the carbonyl group CO of Gln to CH2 or CF2 or changing the NH of Ser to CH2 or CF2. The octapeptide thus modified might become an effective inhibitor or a potential drug candidate against SARS.
DOI: 10.1016/j.ab.2004.10.003
PubMed: 15691506
Affiliations:
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Le document en format XML
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D" first="Dongqing" last="Wei">Dongqing Wei</name></author><author><name sortKey="Sirois, Suzanne" sort="Sirois, Suzanne" uniqKey="Sirois S" first="Suzanne" last="Sirois">Suzanne Sirois</name></author><author><name sortKey="Chou, Kuo Chen" sort="Chou, Kuo Chen" uniqKey="Chou K" first="Kuo-Chen" last="Chou">Kuo-Chen Chou</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2005">2005</date><idno type="RBID">pubmed:15691506</idno><idno type="pmid">15691506</idno><idno type="doi">10.1016/j.ab.2004.10.003</idno><idno type="wicri:Area/PubMed/Corpus">002906</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002906</idno><idno type="wicri:Area/PubMed/Curation">002906</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002906</idno><idno type="wicri:Area/PubMed/Checkpoint">002616</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002616</idno><idno 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xml:lang="en"><term>Acute Disease</term><term>Enzyme Inhibitors (chemistry)</term><term>Enzyme Inhibitors (isolation & purification)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Peptide Hydrolases (metabolism)</term><term>Protein Structure, Tertiary</term><term>Quantum Theory</term><term>SARS Virus (drug effects)</term><term>SARS Virus (enzymology)</term><term>Severe Acute Respiratory Syndrome (drug therapy)</term><term>Severe Acute Respiratory Syndrome (virology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antienzymes ()</term><term>Antienzymes (isolement et purification)</term><term>Antienzymes (pharmacologie)</term><term>Interactions hydrophobes et hydrophiles</term><term>Maladie aigüe</term><term>Modèles moléculaires</term><term>Peptide hydrolases (métabolisme)</term><term>Structure moléculaire</term><term>Structure tertiaire des protéines</term><term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Théorie quantique</term><term>Virus du SRAS ()</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" 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Molecular</term><term>Molecular Structure</term><term>Protein Structure, Tertiary</term><term>Quantum Theory</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antienzymes</term><term>Interactions hydrophobes et hydrophiles</term><term>Maladie aigüe</term><term>Modèles moléculaires</term><term>Structure moléculaire</term><term>Structure tertiaire des protéines</term><term>Théorie quantique</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) is a respiratory disease caused by a newly found virus, called SARS coronavirus. In this study, the cleavage mechanism of the SARS coronavirus main proteinase (Mpro or 3CLpro) on the octapeptide NH2-AVLQ downward arrowSGFR-COOH was investigated using molecular mechanics and quantum mechanics simulations based on the experimental structure of the proteinase. It has been observed that the catalytic dyad (His-41/Cys-145) site between domains I and II attracts the pi electron density from the peptide bond Gln-Ser, increasing the positive charge on C(CO) of Gln and the negative charge on N(NH) of Ser, so as to weaken the Gln-Ser peptide bond. The catalytic functional group is the imidazole group of His-41 and the S in Cys-145. Ndelta1 on the imidazole ring plays the acid-base catalytic role. Based on the "distorted key theory" [K.C. Chou, Anal. Biochem. 233 (1996) 1-14], the possibility to convert the octapeptide to a competent inhibitor has been studied. It has been found that the chemical bond between Gln and Ser will become much stronger and no longer cleavable by the SARS enzyme after either changing the carbonyl group CO of Gln to CH2 or CF2 or changing the NH of Ser to CH2 or CF2. The octapeptide thus modified might become an effective inhibitor or a potential drug candidate against SARS.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Tianjin</li></settlement></list><tree><noCountry><name sortKey="Chou, Kuo Chen" sort="Chou, Kuo Chen" uniqKey="Chou K" first="Kuo-Chen" last="Chou">Kuo-Chen Chou</name><name sortKey="Sirois, Suzanne" sort="Sirois, Suzanne" uniqKey="Sirois S" first="Suzanne" last="Sirois">Suzanne Sirois</name><name sortKey="Wang, Shuqing" sort="Wang, Shuqing" uniqKey="Wang S" first="Shuqing" last="Wang">Shuqing Wang</name><name sortKey="Wei, Dongqing" sort="Wei, Dongqing" uniqKey="Wei D" first="Dongqing" last="Wei">Dongqing Wei</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Du, Qishi" sort="Du, Qishi" uniqKey="Du Q" first="Qishi" last="Du">Qishi Du</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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