Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.
Identifieur interne : 001686 ( PubMed/Corpus ); précédent : 001685; suivant : 001687Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.
Auteurs : Arun K. Ghosh ; Jun Takayama ; Kalapala Venkateswara Rao ; Kiira Ratia ; Rima Chaudhuri ; Debbie C. Mulhearn ; Hyun Lee ; Daniel B. Nichols ; Surendranath Baliji ; Susan C. Baker ; Michael E. Johnson ; Andrew D. MesecarSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2010.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (metabolism), Antiviral Agents (pharmacology), Chlorocebus aethiops, Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Enzyme Inhibitors (chemical synthesis), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (metabolism), Enzyme Inhibitors (pharmacology), Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mass Spectrometry, Models, Molecular, Piperidines (chemical synthesis), Piperidines (chemistry), Piperidines (metabolism), Piperidines (pharmacology), SARS Virus (enzymology), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (virology), Structure-Activity Relationship, Vero Cells, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (metabolism), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Antiviral Agents, Enzyme Inhibitors, Piperidines.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Enzyme Inhibitors, Piperidines, Viral Proteins.
- chemical , metabolism : Antiviral Agents, Cysteine Endopeptidases, Enzyme Inhibitors, Piperidines, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Enzyme Inhibitors, Piperidines.
- drug effects : Virus Replication.
- drug therapy : Severe Acute Respiratory Syndrome.
- enzymology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Animals, Chlorocebus aethiops, Crystallography, X-Ray, Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mass Spectrometry, Models, Molecular, Structure-Activity Relationship, Vero Cells.
Abstract
The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.
DOI: 10.1021/jm1004489
PubMed: 20527968
Links to Exploration step
pubmed:20527968Le document en format XML
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Mulhearn</name></author><author><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name></author><author><name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B" last="Nichols">Daniel B. Nichols</name></author><author><name sortKey="Baliji, Surendranath" sort="Baliji, Surendranath" uniqKey="Baliji S" first="Surendranath" last="Baliji">Surendranath Baliji</name></author><author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</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><author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2010" type="published">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (metabolism)</term><term>Antiviral Agents (pharmacology)</term><term>Chlorocebus aethiops</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Enzyme Inhibitors (chemical synthesis)</term><term>Enzyme Inhibitors (chemistry)</term><term>Enzyme Inhibitors (metabolism)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Inhibitory Concentration 50</term><term>Magnetic Resonance Spectroscopy</term><term>Mass Spectrometry</term><term>Models, Molecular</term><term>Piperidines (chemical synthesis)</term><term>Piperidines (chemistry)</term><term>Piperidines (metabolism)</term><term>Piperidines (pharmacology)</term><term>SARS Virus (enzymology)</term><term>Severe Acute Respiratory Syndrome (drug therapy)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Structure-Activity Relationship</term><term>Vero Cells</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (metabolism)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term><term>Enzyme Inhibitors</term><term>Piperidines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Endopeptidases</term><term>Enzyme Inhibitors</term><term>Piperidines</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Endopeptidases</term><term>Enzyme Inhibitors</term><term>Piperidines</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Enzyme Inhibitors</term><term>Piperidines</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Chlorocebus aethiops</term><term>Crystallography, X-Ray</term><term>Inhibitory Concentration 50</term><term>Magnetic Resonance Spectroscopy</term><term>Mass Spectrometry</term><term>Models, Molecular</term><term>Structure-Activity Relationship</term><term>Vero Cells</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">20527968</PMID><DateCompleted><Year>2010</Year><Month>07</Month><Day>22</Day></DateCompleted><DateRevised><Year>2020</Year><Month>03</Month><Day>25</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4804</ISSN><JournalIssue CitedMedium="Internet"><Volume>53</Volume><Issue>13</Issue><PubDate><Year>2010</Year><Month>Jul</Month><Day>08</Day></PubDate></JournalIssue><Title>Journal of medicinal chemistry</Title><ISOAbbreviation>J. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.</ArticleTitle><Pagination><MedlinePgn>4968-79</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/jm1004489</ELocationID><Abstract><AbstractText>The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ghosh</LastName><ForeName>Arun K</ForeName><Initials>AK</Initials><AffiliationInfo><Affiliation>Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Takayama</LastName><ForeName>Jun</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Rao</LastName><ForeName>Kalapala Venkateswara</ForeName><Initials>KV</Initials></Author><Author ValidYN="Y"><LastName>Ratia</LastName><ForeName>Kiira</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Chaudhuri</LastName><ForeName>Rima</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Mulhearn</LastName><ForeName>Debbie C</ForeName><Initials>DC</Initials></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Hyun</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Nichols</LastName><ForeName>Daniel B</ForeName><Initials>DB</Initials></Author><Author ValidYN="Y"><LastName>Baliji</LastName><ForeName>Surendranath</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Baker</LastName><ForeName>Susan C</ForeName><Initials>SC</Initials></Author><Author ValidYN="Y"><LastName>Johnson</LastName><ForeName>Michael E</ForeName><Initials>ME</Initials></Author><Author ValidYN="Y"><LastName>Mesecar</LastName><ForeName>Andrew D</ForeName><Initials>AD</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P01 AI060915</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P01 AI060915-050003</GrantID><Acronym>AI</Acronym><Agency>NIAID 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><Grant><GrantID>P01AI060915</GrantID><Acronym>AI</Acronym><Agency>NIAID 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="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Med Chem</MedlineTA><NlmUniqueID>9716531</NlmUniqueID><ISSNLinking>0022-2623</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004791">Enzyme Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010880">Piperidines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014764">Viral Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.-</RegistryNumber><NameOfSubstance UI="C099456">3C-like proteinase, Coronavirus</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.-</RegistryNumber><NameOfSubstance UI="D003546">Cysteine Endopeptidases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002522" MajorTopicYN="N">Chlorocebus aethiops</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003546" MajorTopicYN="N">Cysteine Endopeptidases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004791" MajorTopicYN="N">Enzyme Inhibitors</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000378" 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MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045169" MajorTopicYN="N">Severe Acute Respiratory Syndrome</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014709" MajorTopicYN="N">Vero Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014764" MajorTopicYN="N">Viral Proteins</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" 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