Synergistic inhibitor binding to the papain-like protease of human SARS coronavirus: mechanistic and inhibitor design implications.
Identifieur interne : 001850 ( Main/Exploration ); précédent : 001849; suivant : 001851Synergistic inhibitor binding to the papain-like protease of human SARS coronavirus: mechanistic and inhibitor design implications.
Auteurs : Hyun Lee [États-Unis] ; Shuyi Cao ; Kirk E. Hevener ; Lena Truong ; Joseph L. Gatuz ; Kavankumar Patel ; Arun K. Ghosh ; Michael E. JohnsonSource :
- ChemMedChem [ 1860-7187 ] ; 2013.
Descripteurs français
- KwdFr :
- Antiviraux (), Antiviraux (métabolisme), Bibliothèques de petites molécules (), Bibliothèques de petites molécules (métabolisme), Cinétique, Conception de médicament, Cysteine endopeptidases (métabolisme), Humains, Inhibiteurs de protéases (), Inhibiteurs de protéases (métabolisme), Liaison aux protéines, Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Résonance plasmonique de surface, Simulation de docking moléculaire, Sites de fixation, Structure tertiaire des protéines, Synergie des médicaments, Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- métabolisme : Antiviraux, Bibliothèques de petites molécules, Cysteine endopeptidases, Inhibiteurs de protéases, Protéines virales.
- Antiviraux, Bibliothèques de petites molécules, Cinétique, Conception de médicament, Humains, Inhibiteurs de protéases, Liaison aux protéines, Résonance plasmonique de surface, Simulation de docking moléculaire, Sites de fixation, Structure tertiaire des protéines, Synergie des médicaments.
English descriptors
- KwdEn :
- Antiviral Agents (chemistry), Antiviral Agents (metabolism), Binding Sites, Cysteine Endopeptidases (metabolism), Drug Design, Drug Synergism, Humans, Kinetics, Molecular Docking Simulation, Protease Inhibitors (chemistry), Protease Inhibitors (metabolism), Protein Binding, Protein Structure, Tertiary, SARS Virus (enzymology), Small Molecule Libraries (chemistry), Small Molecule Libraries (metabolism), Surface Plasmon Resonance, Viral Proteins (antagonists & inhibitors), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Antiviral Agents, Protease Inhibitors, Small Molecule Libraries.
- chemical , metabolism : Antiviral Agents, Cysteine Endopeptidases, Protease Inhibitors, Small Molecule Libraries, Viral Proteins.
- enzymology : SARS Virus.
- Binding Sites, Drug Design, Drug Synergism, Humans, Kinetics, Molecular Docking Simulation, Protein Binding, Protein Structure, Tertiary, Surface Plasmon Resonance.
Abstract
We previously developed two potent chemical classes that inhibit the essential papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus. In this study, we applied a novel approach to identify small fragments that act synergistically with these inhibitors. A fragment library was screened in combination with four previously developed lead inhibitors by fluorescence-based enzymatic assays. Several fragment compounds synergistically enhanced the inhibitory activity of the lead inhibitors by approximately an order of magnitude. Surface plasmon resonance measurements showed that three fragments bind specifically to the PLpro enzyme. Mode of inhibition, computational solvent mapping, and molecular docking studies suggest that these fragments bind adjacent to the binding site of the lead inhibitors and further stabilize the inhibitor-bound state. We propose potential next-generation compounds based on a computational fragment-merging approach. This approach provides an alternative strategy for lead optimization for cases in which direct co-crystallization is difficult.
DOI: 10.1002/cmdc.201300134
PubMed: 23788528
Affiliations:
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Le document en format XML
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Hevener</name></author><author><name sortKey="Truong, Lena" sort="Truong, Lena" uniqKey="Truong L" first="Lena" last="Truong">Lena Truong</name></author><author><name sortKey="Gatuz, Joseph L" sort="Gatuz, Joseph L" uniqKey="Gatuz J" first="Joseph L" last="Gatuz">Joseph L. Gatuz</name></author><author><name sortKey="Patel, Kavankumar" sort="Patel, Kavankumar" uniqKey="Patel K" first="Kavankumar" last="Patel">Kavankumar Patel</name></author><author><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K" last="Ghosh">Arun K. Ghosh</name></author><author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E" last="Johnson">Michael E. Johnson</name></author></analytic><series><title level="j">ChemMedChem</title><idno type="eISSN">1860-7187</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (metabolism)</term><term>Binding Sites</term><term>Cysteine Endopeptidases (metabolism)</term><term>Drug Design</term><term>Drug Synergism</term><term>Humans</term><term>Kinetics</term><term>Molecular Docking Simulation</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (metabolism)</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>SARS Virus (enzymology)</term><term>Small Molecule Libraries (chemistry)</term><term>Small Molecule Libraries (metabolism)</term><term>Surface Plasmon Resonance</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antiviraux ()</term><term>Antiviraux (métabolisme)</term><term>Bibliothèques de petites molécules ()</term><term>Bibliothèques de petites molécules (métabolisme)</term><term>Cinétique</term><term>Conception de médicament</term><term>Cysteine endopeptidases (métabolisme)</term><term>Humains</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (métabolisme)</term><term>Liaison aux protéines</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Protéines virales (métabolisme)</term><term>Résonance plasmonique de surface</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Synergie des médicaments</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>Antiviral Agents</term><term>Protease Inhibitors</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Endopeptidases</term><term>Protease Inhibitors</term><term>Small Molecule Libraries</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>Antiviraux</term><term>Bibliothèques de petites molécules</term><term>Cysteine endopeptidases</term><term>Inhibiteurs de protéases</term><term>Protéines virales</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Drug Design</term><term>Drug Synergism</term><term>Humans</term><term>Kinetics</term><term>Molecular Docking Simulation</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Surface Plasmon Resonance</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term><term>Bibliothèques de petites molécules</term><term>Cinétique</term><term>Conception de médicament</term><term>Humains</term><term>Inhibiteurs de protéases</term><term>Liaison aux protéines</term><term>Résonance plasmonique de surface</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Synergie des médicaments</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We previously developed two potent chemical classes that inhibit the essential papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus. In this study, we applied a novel approach to identify small fragments that act synergistically with these inhibitors. A fragment library was screened in combination with four previously developed lead inhibitors by fluorescence-based enzymatic assays. Several fragment compounds synergistically enhanced the inhibitory activity of the lead inhibitors by approximately an order of magnitude. Surface plasmon resonance measurements showed that three fragments bind specifically to the PLpro enzyme. Mode of inhibition, computational solvent mapping, and molecular docking studies suggest that these fragments bind adjacent to the binding site of the lead inhibitors and further stabilize the inhibitor-bound state. We propose potential next-generation compounds based on a computational fragment-merging approach. This approach provides an alternative strategy for lead optimization for cases in which direct co-crystallization is difficult. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li></region><settlement><li>Chicago</li></settlement><orgName><li>Université de l'Illinois à Chicago</li></orgName></list><tree><noCountry><name sortKey="Cao, Shuyi" sort="Cao, Shuyi" uniqKey="Cao S" first="Shuyi" last="Cao">Shuyi Cao</name><name sortKey="Gatuz, Joseph L" sort="Gatuz, Joseph L" uniqKey="Gatuz J" first="Joseph L" last="Gatuz">Joseph L. Gatuz</name><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K" last="Ghosh">Arun K. Ghosh</name><name sortKey="Hevener, Kirk E" sort="Hevener, Kirk E" uniqKey="Hevener K" first="Kirk E" last="Hevener">Kirk E. Hevener</name><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E" last="Johnson">Michael E. Johnson</name><name sortKey="Patel, Kavankumar" sort="Patel, Kavankumar" uniqKey="Patel K" first="Kavankumar" last="Patel">Kavankumar Patel</name><name sortKey="Truong, Lena" sort="Truong, Lena" uniqKey="Truong L" first="Lena" last="Truong">Lena Truong</name></noCountry><country name="États-Unis"><region name="Illinois"><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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