Computational modeling of the bat HKU4 coronavirus 3CLpro inhibitors as a tool for the development of antivirals against the emerging Middle East respiratory syndrome (MERS) coronavirus.
Identifieur interne : 000E50 ( Main/Exploration ); précédent : 000E49; suivant : 000E51Computational modeling of the bat HKU4 coronavirus 3CLpro inhibitors as a tool for the development of antivirals against the emerging Middle East respiratory syndrome (MERS) coronavirus.
Auteurs : Areej Abuhammad [Jordanie] ; Rua'A A. Al-Aqtash [Jordanie] ; Brandon J. Anson [États-Unis] ; Andrew D. Mesecar [États-Unis] ; Mutasem O. Taha [Jordanie]Source :
- Journal of molecular recognition : JMR [ 1099-1352 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (pharmacologie), Chiroptera (virologie), Coronavirus du syndrome respiratoire du Moyen-Orient (), Courbe ROC, Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Ligands, Modèles moléculaires, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Relation quantitative structure-activité, Reproductibilité des résultats, Simulation numérique, Sites de fixation, Séquence d'acides aminés.
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- pharmacologie : Antiviraux, Inhibiteurs de protéases.
- virologie : Chiroptera.
- Animaux, Coronavirus du syndrome respiratoire du Moyen-Orient, Courbe ROC, Inhibiteurs de protéases, Ligands, Modèles moléculaires, Protéines virales, Relation quantitative structure-activité, Reproductibilité des résultats, Simulation numérique, Sites de fixation, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Antiviral Agents (pharmacology), Betacoronavirus (drug effects), Betacoronavirus (enzymology), Binding Sites, Chiroptera (virology), Computer Simulation, Ligands, Middle East Respiratory Syndrome Coronavirus (drug effects), Models, Molecular, Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), Quantitative Structure-Activity Relationship, ROC Curve, Reproducibility of Results, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Protease Inhibitors, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Protease Inhibitors.
- drug effects : Betacoronavirus, Middle East Respiratory Syndrome Coronavirus.
- enzymology : Betacoronavirus.
- virology : Chiroptera.
- Amino Acid Sequence, Animals, Binding Sites, Computer Simulation, Ligands, Models, Molecular, Quantitative Structure-Activity Relationship, ROC Curve, Reproducibility of Results.
Abstract
The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus that poses a major challenge to clinical management. The 3C-like protease (3CLpro ) is essential for viral replication and thus represents a potential target for antiviral drug development. Presently, very few data are available on MERS-CoV 3CLpro inhibition by small molecules. We conducted extensive exploration of the pharmacophoric space of a recently identified set of peptidomimetic inhibitors of the bat HKU4-CoV 3CLpro . HKU4-CoV 3CLpro shares high sequence identity (81%) with the MERS-CoV enzyme and thus represents a potential surrogate model for anti-MERS drug discovery. We used 2 well-established methods: Quantitative structure-activity relationship (QSAR)-guided modeling and docking-based comparative intermolecular contacts analysis. The established pharmacophore models highlight structural features needed for ligand recognition and revealed important binding-pocket regions involved in 3CLpro -ligand interactions. The best models were used as 3D queries to screen the National Cancer Institute database for novel nonpeptidomimetic 3CLpro inhibitors. The identified hits were tested for HKU4-CoV and MERS-CoV 3CLpro inhibition. Two hits, which share the phenylsulfonamide fragment, showed moderate inhibitory activity against the MERS-CoV 3CLpro and represent a potential starting point for the development of novel anti-MERS agents. To the best of our knowledge, this is the first pharmacophore modeling study supported by in vitro validation on the MERS-CoV 3CLpro .
DOI: 10.1002/jmr.2644
PubMed: 28608547
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000C64
- to stream PubMed, to step Curation: 000C64
- to stream PubMed, to step Checkpoint: 000D57
- to stream Ncbi, to step Merge: 001A70
- to stream Ncbi, to step Curation: 001A70
- to stream Ncbi, to step Checkpoint: 001A70
- to stream Main, to step Merge: 000E53
- to stream Main, to step Curation: 000E50
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Computational modeling of the bat HKU4 coronavirus 3CL<sup>pro</sup> inhibitors as a tool for the development of antivirals against the emerging Middle East respiratory syndrome (MERS) coronavirus.</title><author><name sortKey="Abuhammad, Areej" sort="Abuhammad, Areej" uniqKey="Abuhammad A" first="Areej" last="Abuhammad">Areej Abuhammad</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman</wicri:regionArea><wicri:noRegion>Amman</wicri:noRegion></affiliation></author><author><name sortKey="Al Aqtash, Rua A A" sort="Al Aqtash, Rua A A" uniqKey="Al Aqtash R" first="Rua'A A" last="Al-Aqtash">Rua'A A. Al-Aqtash</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman</wicri:regionArea><wicri:noRegion>Amman</wicri:noRegion></affiliation></author><author><name sortKey="Anson, Brandon J" sort="Anson, Brandon J" uniqKey="Anson B" first="Brandon J" last="Anson">Brandon J. Anson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Purdue University, West Lafayette, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Purdue University, West Lafayette, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Taha, Mutasem O" sort="Taha, Mutasem O" uniqKey="Taha M" first="Mutasem O" last="Taha">Mutasem O. Taha</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman</wicri:regionArea><wicri:noRegion>Amman</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28608547</idno><idno type="pmid">28608547</idno><idno type="doi">10.1002/jmr.2644</idno><idno type="wicri:Area/PubMed/Corpus">000C64</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000C64</idno><idno type="wicri:Area/PubMed/Curation">000C64</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000C64</idno><idno type="wicri:Area/PubMed/Checkpoint">000D57</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000D57</idno><idno type="wicri:Area/Ncbi/Merge">001A70</idno><idno type="wicri:Area/Ncbi/Curation">001A70</idno><idno type="wicri:Area/Ncbi/Checkpoint">001A70</idno><idno type="wicri:Area/Main/Merge">000E53</idno><idno type="wicri:Area/Main/Curation">000E50</idno><idno type="wicri:Area/Main/Exploration">000E50</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Computational modeling of the bat HKU4 coronavirus 3CL<sup>pro</sup> inhibitors as a tool for the development of antivirals against the emerging Middle East respiratory syndrome (MERS) coronavirus.</title><author><name sortKey="Abuhammad, Areej" sort="Abuhammad, Areej" uniqKey="Abuhammad A" first="Areej" last="Abuhammad">Areej Abuhammad</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman</wicri:regionArea><wicri:noRegion>Amman</wicri:noRegion></affiliation></author><author><name sortKey="Al Aqtash, Rua A A" sort="Al Aqtash, Rua A A" uniqKey="Al Aqtash R" first="Rua'A A" last="Al-Aqtash">Rua'A A. Al-Aqtash</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman</wicri:regionArea><wicri:noRegion>Amman</wicri:noRegion></affiliation></author><author><name sortKey="Anson, Brandon J" sort="Anson, Brandon J" uniqKey="Anson B" first="Brandon J" last="Anson">Brandon J. Anson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Purdue University, West Lafayette, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Purdue University, West Lafayette, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Taha, Mutasem O" sort="Taha, Mutasem O" uniqKey="Taha M" first="Mutasem O" last="Taha">Mutasem O. Taha</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman</wicri:regionArea><wicri:noRegion>Amman</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of molecular recognition : JMR</title><idno type="eISSN">1099-1352</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Betacoronavirus (drug effects)</term><term>Betacoronavirus (enzymology)</term><term>Binding Sites</term><term>Chiroptera (virology)</term><term>Computer Simulation</term><term>Ligands</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Models, Molecular</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (pharmacology)</term><term>Quantitative Structure-Activity Relationship</term><term>ROC Curve</term><term>Reproducibility of Results</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Chiroptera (virologie)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Courbe ROC</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Ligands</term><term>Modèles moléculaires</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Relation quantitative structure-activité</term><term>Reproductibilité des résultats</term><term>Simulation numérique</term><term>Sites de fixation</term><term>Séquence d'acides aminés</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>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Betacoronavirus</term><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Chiroptera</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Chiroptera</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Binding Sites</term><term>Computer Simulation</term><term>Ligands</term><term>Models, Molecular</term><term>Quantitative Structure-Activity Relationship</term><term>ROC Curve</term><term>Reproducibility of Results</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Courbe ROC</term><term>Inhibiteurs de protéases</term><term>Ligands</term><term>Modèles moléculaires</term><term>Protéines virales</term><term>Relation quantitative structure-activité</term><term>Reproductibilité des résultats</term><term>Simulation numérique</term><term>Sites de fixation</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus that poses a major challenge to clinical management. The 3C-like protease (3CL<sup>pro</sup> ) is essential for viral replication and thus represents a potential target for antiviral drug development. Presently, very few data are available on MERS-CoV 3CL<sup>pro</sup> inhibition by small molecules. We conducted extensive exploration of the pharmacophoric space of a recently identified set of peptidomimetic inhibitors of the bat HKU4-CoV 3CL<sup>pro</sup> . HKU4-CoV 3CL<sup>pro</sup> shares high sequence identity (81%) with the MERS-CoV enzyme and thus represents a potential surrogate model for anti-MERS drug discovery. We used 2 well-established methods: Quantitative structure-activity relationship (QSAR)-guided modeling and docking-based comparative intermolecular contacts analysis. The established pharmacophore models highlight structural features needed for ligand recognition and revealed important binding-pocket regions involved in 3CL<sup>pro</sup> -ligand interactions. The best models were used as 3D queries to screen the National Cancer Institute database for novel nonpeptidomimetic 3CL<sup>pro</sup> inhibitors. The identified hits were tested for HKU4-CoV and MERS-CoV 3CL<sup>pro</sup> inhibition. Two hits, which share the phenylsulfonamide fragment, showed moderate inhibitory activity against the MERS-CoV 3CL<sup>pro</sup> and represent a potential starting point for the development of novel anti-MERS agents. To the best of our knowledge, this is the first pharmacophore modeling study supported by in vitro validation on the MERS-CoV 3CL<sup>pro</sup> .</div></front></TEI><affiliations><list><country><li>Jordanie</li><li>États-Unis</li></country><region><li>Indiana</li></region></list><tree><country name="Jordanie"><noRegion><name sortKey="Abuhammad, Areej" sort="Abuhammad, Areej" uniqKey="Abuhammad A" first="Areej" last="Abuhammad">Areej Abuhammad</name></noRegion><name sortKey="Al Aqtash, Rua A A" sort="Al Aqtash, Rua A A" uniqKey="Al Aqtash R" first="Rua'A A" last="Al-Aqtash">Rua'A A. Al-Aqtash</name><name sortKey="Taha, Mutasem O" sort="Taha, Mutasem O" uniqKey="Taha M" first="Mutasem O" last="Taha">Mutasem O. Taha</name></country><country name="États-Unis"><region name="Indiana"><name sortKey="Anson, Brandon J" sort="Anson, Brandon J" uniqKey="Anson B" first="Brandon J" last="Anson">Brandon J. Anson</name></region><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/MersV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000E50 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000E50 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= MersV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:28608547
|texte= Computational modeling of the bat HKU4 coronavirus 3CLpro inhibitors as a tool for the development of antivirals against the emerging Middle East respiratory syndrome (MERS) coronavirus.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:28608547" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a MersV1
| This area was generated with Dilib version V0.6.33. |  |