QM/QM studies for Michael reaction in coronavirus main protease (3CL Pro).
Identifieur interne : 001585 ( Main/Exploration ); précédent : 001584; suivant : 001586QM/QM studies for Michael reaction in coronavirus main protease (3CL Pro).
Auteurs : Alex G. Taranto [Brésil] ; Paulo Carvalho ; Mitchell A. AverySource :
- Journal of molecular graphics & modelling [ 1873-4243 ] ; 2008.
Descripteurs français
- KwdFr :
- Catalyse, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Domaine catalytique, Inhibiteurs de protéases (), Liaison hydrogène, Modèles moléculaires, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Reproductibilité des résultats, Thermodynamique, Théorie quantique, Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- métabolisme : Cysteine endopeptidases, Protéines virales.
- Catalyse, Cysteine endopeptidases, Domaine catalytique, Inhibiteurs de protéases, Liaison hydrogène, Modèles moléculaires, Protéines virales, Reproductibilité des résultats, Thermodynamique, Théorie quantique.
English descriptors
- KwdEn :
- Catalysis, Catalytic Domain, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Hydrogen Bonding, Models, Molecular, Protease Inhibitors (chemistry), Quantum Theory, Reproducibility of Results, SARS Virus (enzymology), Thermodynamics, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Cysteine Endopeptidases, Protease Inhibitors, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Viral Proteins.
- enzymology : SARS Virus.
- Catalysis, Catalytic Domain, Hydrogen Bonding, Models, Molecular, Quantum Theory, Reproducibility of Results, Thermodynamics.
Abstract
Severe acute respiratory syndrome (SARS) is an illness caused by a novel corona virus wherein the main proteinase called 3CL(Pro) has been established as a target for drug design. The mechanism of action involves nucleophilic attack by Cys145 present in the active site on the carbonyl carbon of the scissile amide bond of the substrate and the intermediate product is stabilized by hydrogen bonds with the residues of the oxyanion hole. Based on the X-ray structure of 3CL(Pro) co-crystallized with a trans-alpha,beta-unsaturated ethyl ester (Michael acceptor), a set of QM/QM and QM/MM calculations were performed, yielding three models with increasingly higher the number of atoms. A previous validation step was performed using classical theoretical calculation and PROCHECK software. The Michael reaction studies show an exothermic process with -4.5 kcal/mol. During the reaction pathway, an intermediate is formed by hydrogen and water molecule migration from a histidine residue and solvent, respectively. In addition, similar with experimental results, the complex between N3 and 3CL(Pro) is 578 kcal/mol more stable than N1-3CL(Pro) using Own N-layer Integrated molecular Orbital molecular Mechanics (ONIOM) approach. We suggest 3CL(Pro) inhibitors need small polar groups to decrease the energy barrier for alkylation reaction. These results can be useful for the development of new compounds against SARS.
DOI: 10.1016/j.jmgm.2008.05.002
PubMed: 18567519
Affiliations:
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Taranto</name><affiliation wicri:level="2"><nlm:affiliation>Departamento de Saúde, Universidade Estadual de Feira de Santana (UEFS), BA, Brazil. taranto@uefs.br</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Saúde, Universidade Estadual de Feira de Santana (UEFS), BA</wicri:regionArea><placeName><region type="state">Bahia</region></placeName></affiliation></author><author><name sortKey="Carvalho, Paulo" sort="Carvalho, Paulo" uniqKey="Carvalho P" first="Paulo" last="Carvalho">Paulo Carvalho</name></author><author><name sortKey="Avery, Mitchell A" sort="Avery, Mitchell A" uniqKey="Avery M" first="Mitchell A" last="Avery">Mitchell A. Avery</name></author></analytic><series><title level="j">Journal of molecular graphics & modelling</title><idno type="eISSN">1873-4243</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Catalysis</term><term>Catalytic Domain</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Hydrogen Bonding</term><term>Models, Molecular</term><term>Protease Inhibitors (chemistry)</term><term>Quantum Theory</term><term>Reproducibility of Results</term><term>SARS Virus (enzymology)</term><term>Thermodynamics</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Catalyse</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (métabolisme)</term><term>Domaine catalytique</term><term>Inhibiteurs de protéases ()</term><term>Liaison hydrogène</term><term>Modèles moléculaires</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Protéines virales (métabolisme)</term><term>Reproductibilité des résultats</term><term>Thermodynamique</term><term>Théorie quantique</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Proteins</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="métabolisme" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Protéines virales</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Catalysis</term><term>Catalytic Domain</term><term>Hydrogen Bonding</term><term>Models, Molecular</term><term>Quantum Theory</term><term>Reproducibility of Results</term><term>Thermodynamics</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Catalyse</term><term>Cysteine endopeptidases</term><term>Domaine catalytique</term><term>Inhibiteurs de protéases</term><term>Liaison hydrogène</term><term>Modèles moléculaires</term><term>Protéines virales</term><term>Reproductibilité des résultats</term><term>Thermodynamique</term><term>Théorie quantique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) is an illness caused by a novel corona virus wherein the main proteinase called 3CL(Pro) has been established as a target for drug design. The mechanism of action involves nucleophilic attack by Cys145 present in the active site on the carbonyl carbon of the scissile amide bond of the substrate and the intermediate product is stabilized by hydrogen bonds with the residues of the oxyanion hole. Based on the X-ray structure of 3CL(Pro) co-crystallized with a trans-alpha,beta-unsaturated ethyl ester (Michael acceptor), a set of QM/QM and QM/MM calculations were performed, yielding three models with increasingly higher the number of atoms. A previous validation step was performed using classical theoretical calculation and PROCHECK software. The Michael reaction studies show an exothermic process with -4.5 kcal/mol. During the reaction pathway, an intermediate is formed by hydrogen and water molecule migration from a histidine residue and solvent, respectively. In addition, similar with experimental results, the complex between N3 and 3CL(Pro) is 578 kcal/mol more stable than N1-3CL(Pro) using Own N-layer Integrated molecular Orbital molecular Mechanics (ONIOM) approach. We suggest 3CL(Pro) inhibitors need small polar groups to decrease the energy barrier for alkylation reaction. These results can be useful for the development of new compounds against SARS.</div></front></TEI><affiliations><list><country><li>Brésil</li></country><region><li>Bahia</li></region></list><tree><noCountry><name sortKey="Avery, Mitchell A" sort="Avery, Mitchell A" uniqKey="Avery M" first="Mitchell A" last="Avery">Mitchell A. Avery</name><name sortKey="Carvalho, Paulo" sort="Carvalho, Paulo" uniqKey="Carvalho P" first="Paulo" last="Carvalho">Paulo Carvalho</name></noCountry><country name="Brésil"><region name="Bahia"><name sortKey="Taranto, Alex G" sort="Taranto, Alex G" uniqKey="Taranto A" first="Alex G" last="Taranto">Alex G. 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