Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease.
Identifieur interne : 001853 ( PubMed/Curation ); précédent : 001852; suivant : 001854Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease.
Auteurs : Arun K. Ghosh [États-Unis] ; Jun Takayama ; Yoann Aubin ; Kiira Ratia ; Rima Chaudhuri ; Yahira Baez ; Katrina Sleeman ; Melissa Coughlin ; Daniel B. Nichols ; Debbie C. Mulhearn ; Bellur S. Prabhakar ; Susan C. Baker ; Michael E. Johnson ; Andrew D. MesecarSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2009.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Benzamides (), Benzamides (pharmacologie), Benzamides (synthèse chimique), Cellules Vero, Conception de médicament, Cristallographie aux rayons X, Cysteine endopeptidases, Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Inhibiteurs de protéases (synthèse chimique), Modèles moléculaires, Naphtalènes (), Naphtalènes (pharmacologie), Naphtalènes (synthèse chimique), Protéines virales (antagonistes et inhibiteurs), Relation quantitative structure-activité, Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- pharmacologie : Antiviraux, Benzamides, Inhibiteurs de protéases, Naphtalènes.
- synthèse chimique : Antiviraux, Benzamides, Inhibiteurs de protéases, Naphtalènes.
- Animaux, Antiviraux, Benzamides, Cellules Vero, Conception de médicament, Cristallographie aux rayons X, Cysteine endopeptidases, Inhibiteurs de protéases, Modèles moléculaires, Naphtalènes, Relation quantitative structure-activité, Virus du SRAS.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Benzamides (chemical synthesis), Benzamides (chemistry), Benzamides (pharmacology), Chlorocebus aethiops, Crystallography, X-Ray, Cysteine Endopeptidases, Drug Design, Models, Molecular, Naphthalenes (chemical synthesis), Naphthalenes (chemistry), Naphthalenes (pharmacology), Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), Quantitative Structure-Activity Relationship, SARS Virus (drug effects), SARS Virus (enzymology), Vero Cells, Viral Proteins (antagonists & inhibitors).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Antiviral Agents, Benzamides, Naphthalenes, Protease Inhibitors.
- chemical , chemistry : Antiviral Agents, Benzamides, Naphthalenes, Protease Inhibitors.
- chemical , pharmacology : Antiviral Agents, Benzamides, Naphthalenes, Protease Inhibitors.
- drug effects : SARS Virus.
- enzymology : SARS Virus.
- Animals, Chlorocebus aethiops, Crystallography, X-Ray, Cysteine Endopeptidases, Drug Design, Models, Molecular, Quantitative Structure-Activity Relationship, Vero Cells.
Abstract
We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.
DOI: 10.1021/jm900611t
PubMed: 19645480
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Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">19645480</PMID><DateCompleted><Year>2010</Year><Month>07</Month><Day>01</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>52</Volume><Issue>16</Issue><PubDate><Year>2009</Year><Month>Aug</Month><Day>27</Day></PubDate></JournalIssue><Title>Journal of medicinal chemistry</Title><ISOAbbreviation>J. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease.</ArticleTitle><Pagination><MedlinePgn>5228-40</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/jm900611t</ELocationID><Abstract><AbstractText>We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ghosh</LastName><ForeName>Arun K</ForeName><Initials>AK</Initials><AffiliationInfo><Affiliation>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 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>Aubin</LastName><ForeName>Yoann</ForeName><Initials>Y</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>Baez</LastName><ForeName>Yahira</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Sleeman</LastName><ForeName>Katrina</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Coughlin</LastName><ForeName>Melissa</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Nichols</LastName><ForeName>Daniel B</ForeName><Initials>DB</Initials></Author><Author ValidYN="Y"><LastName>Mulhearn</LastName><ForeName>Debbie C</ForeName><Initials>DC</Initials></Author><Author ValidYN="Y"><LastName>Prabhakar</LastName><ForeName>Bellur S</ForeName><Initials>BS</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 AI060915-05</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></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</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="D001549">Benzamides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C550443">N-methyl-5-methylamino-2-methyl-N-((R)-1-(1-naphthyl)ethy)benzamide</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009281">Naphthalenes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011480">Protease Inhibitors</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="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001549" MajorTopicYN="N">Benzamides</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</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></MeshHeading><MeshHeading><DescriptorName UI="D015195" MajorTopicYN="N">Drug Design</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009281" MajorTopicYN="N">Naphthalenes</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011480" MajorTopicYN="N">Protease Inhibitors</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D021281" MajorTopicYN="N">Quantitative Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName></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></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2009</Year><Month>8</Month><Day>4</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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