Synergistic inhibitor binding to the papain-like protease of human SARS coronavirus: mechanistic and inhibitor design implications.
Identifieur interne : 001179 ( PubMed/Corpus ); précédent : 001178; suivant : 001180Synergistic inhibitor binding to the papain-like protease of human SARS coronavirus: mechanistic and inhibitor design implications.
Auteurs : Hyun Lee ; Shuyi Cao ; Kirk E. Hevener ; Lena Truong ; Joseph L. Gatuz ; Kavankumar Patel ; Arun K. Ghosh ; Michael E. JohnsonSource :
- ChemMedChem [ 1860-7187 ] ; 2013.
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
Links to Exploration step
pubmed:23788528Le 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. 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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="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="enzymology" xml:lang="en"><term>SARS Virus</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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">23788528</PMID><DateCompleted><Year>2014</Year><Month>02</Month><Day>21</Day></DateCompleted><DateRevised><Year>2020</Year><Month>03</Month><Day>25</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1860-7187</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>8</Issue><PubDate><Year>2013</Year><Month>Aug</Month></PubDate></JournalIssue><Title>ChemMedChem</Title><ISOAbbreviation>ChemMedChem</ISOAbbreviation></Journal><ArticleTitle>Synergistic inhibitor binding to the papain-like protease of human SARS coronavirus: mechanistic and inhibitor design implications.</ArticleTitle><Pagination><MedlinePgn>1361-72</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/cmdc.201300134</ELocationID><Abstract><AbstractText>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. </AbstractText><CopyrightInformation>Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Hyun</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60607, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cao</LastName><ForeName>Shuyi</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Hevener</LastName><ForeName>Kirk E</ForeName><Initials>KE</Initials></Author><Author ValidYN="Y"><LastName>Truong</LastName><ForeName>Lena</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Gatuz</LastName><ForeName>Joseph L</ForeName><Initials>JL</Initials></Author><Author ValidYN="Y"><LastName>Patel</LastName><ForeName>Kavankumar</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Ghosh</LastName><ForeName>Arun K</ForeName><Initials>AK</Initials></Author><Author ValidYN="Y"><LastName>Johnson</LastName><ForeName>Michael E</ForeName><Initials>ME</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R56 AI089535</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>5T32-DE018381</GrantID><Acronym>DE</Acronym><Agency>NIDCR NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>T32 DE018381</GrantID><Acronym>DE</Acronym><Agency>NIDCR NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P41 RR001081</GrantID><Acronym>RR</Acronym><Agency>NCRR NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R37 GM053386</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2013</Year><Month>06</Month><Day>20</Day></ArticleDate></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>ChemMedChem</MedlineTA><NlmUniqueID>101259013</NlmUniqueID><ISSNLinking>1860-7179</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011480">Protease Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D054852">Small Molecule Libraries</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014764">Viral 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