Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety.
Identifieur interne : 002600 ( Ncbi/Merge ); précédent : 002599; suivant : 002601Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety.
Auteurs : Sho Konno [Japon] ; Pillaiyar Thanigaimalai ; Takehito Yamamoto ; Kiyohiko Nakada ; Rie Kakiuchi ; Kentaro Takayama ; Yuri Yamazaki ; Fumika Yakushiji ; Kenichi Akaji ; Yoshiaki Kiso ; Yuko Kawasaki ; Shen-En Chen ; Ernesto Freire ; Yoshio HayashiSource :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2013.
Descripteurs français
- KwdFr :
- Benzothiazoles (), Conception de médicament, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Inhibiteurs de protéases (), Inhibiteurs de protéases (métabolisme), Inhibiteurs de protéases (synthèse chimique), Liaison aux protéines, Liaison hydrogène, Oligopeptides (), Oligopeptides (métabolisme), Oligopeptides (synthèse chimique), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Relation structure-activité, Simulation de docking moléculaire, Sites de fixation, Structure tertiaire des protéines, Virus du SRAS (métabolisme).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- métabolisme : Cysteine endopeptidases, Inhibiteurs de protéases, Oligopeptides, Protéines virales, Virus du SRAS.
- synthèse chimique : Inhibiteurs de protéases, Oligopeptides.
- Benzothiazoles, Conception de médicament, Cysteine endopeptidases, Inhibiteurs de protéases, Liaison aux protéines, Liaison hydrogène, Oligopeptides, Relation structure-activité, Simulation de docking moléculaire, Sites de fixation, Structure tertiaire des protéines.
English descriptors
- KwdEn :
- Benzothiazoles (chemistry), Binding Sites, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Drug Design, Hydrogen Bonding, Molecular Docking Simulation, Oligopeptides (chemical synthesis), Oligopeptides (chemistry), Oligopeptides (metabolism), Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (metabolism), Protein Binding, Protein Structure, Tertiary, SARS Virus (metabolism), Structure-Activity Relationship, Viral Proteins (antagonists & inhibitors), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Oligopeptides, Protease Inhibitors.
- chemical , chemistry : Benzothiazoles, Cysteine Endopeptidases, Oligopeptides, Protease Inhibitors.
- chemical , metabolism : Cysteine Endopeptidases, Oligopeptides, Protease Inhibitors, Viral Proteins.
- metabolism : SARS Virus.
- Binding Sites, Drug Design, Hydrogen Bonding, Molecular Docking Simulation, Protein Binding, Protein Structure, Tertiary, Structure-Activity Relationship.
Abstract
We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.
DOI: 10.1016/j.bmc.2012.11.017
PubMed: 23245752
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 001274
- to stream PubMed, to step Curation: 001274
- to stream PubMed, to step Checkpoint: 001202
Links to Exploration step
pubmed:23245752Le document en format XML
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docking moléculaire</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">23245752</PMID><DateCompleted><Year>2013</Year><Month>06</Month><Day>05</Day></DateCompleted><DateRevised><Year>2020</Year><Month>04</Month><Day>09</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1464-3391</ISSN><JournalIssue CitedMedium="Internet"><Volume>21</Volume><Issue>2</Issue><PubDate><Year>2013</Year><Month>Jan</Month><Day>15</Day></PubDate></JournalIssue><Title>Bioorganic & medicinal chemistry</Title><ISOAbbreviation>Bioorg. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety.</ArticleTitle><Pagination><MedlinePgn>412-24</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.bmc.2012.11.017</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0968-0896(12)00901-7</ELocationID><Abstract><AbstractText>We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.</AbstractText><CopyrightInformation>Copyright © 2012 Elsevier Ltd. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Konno</LastName><ForeName>Sho</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thanigaimalai</LastName><ForeName>Pillaiyar</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Yamamoto</LastName><ForeName>Takehito</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Nakada</LastName><ForeName>Kiyohiko</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Kakiuchi</LastName><ForeName>Rie</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Takayama</LastName><ForeName>Kentaro</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Yamazaki</LastName><ForeName>Yuri</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Yakushiji</LastName><ForeName>Fumika</ForeName><Initials>F</Initials></Author><Author ValidYN="Y"><LastName>Akaji</LastName><ForeName>Kenichi</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Kiso</LastName><ForeName>Yoshiaki</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Kawasaki</LastName><ForeName>Yuko</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Shen-En</ForeName><Initials>SE</Initials></Author><Author ValidYN="Y"><LastName>Freire</LastName><ForeName>Ernesto</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Hayashi</LastName><ForeName>Yoshio</ForeName><Initials>Y</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>11</Month><Day>24</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Bioorg Med Chem</MedlineTA><NlmUniqueID>9413298</NlmUniqueID><ISSNLinking>0968-0896</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D052160">Benzothiazoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009842">Oligopeptides</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="D003546">Cysteine Endopeptidases</NameOfSubstance></Chemical><Chemical><RegistryNumber>G5BW2593EP</RegistryNumber><NameOfSubstance UI="C005465">benzothiazole</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D052160" MajorTopicYN="N">Benzothiazoles</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001665" MajorTopicYN="N">Binding Sites</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="D015195" MajorTopicYN="Y">Drug Design</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006860" MajorTopicYN="N">Hydrogen Bonding</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D062105" MajorTopicYN="N">Molecular Docking Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009842" MajorTopicYN="N">Oligopeptides</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</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="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017434" MajorTopicYN="N">Protein Structure, Tertiary</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014764" MajorTopicYN="N">Viral Proteins</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2012</Year><Month>10</Month><Day>01</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2012</Year><Month>11</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2012</Year><Month>11</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>6</Month><Day>6</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">23245752</ArticleId><ArticleId IdType="pii">S0968-0896(12)00901-7</ArticleId><ArticleId IdType="doi">10.1016/j.bmc.2012.11.017</ArticleId><ArticleId IdType="pmc">PMC7127713</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Chem Biol. 2004 Sep;11(9):1293-9</Citation><ArticleIdList><ArticleId IdType="pubmed">15380189</ArticleId></ArticleIdList></Reference></ReferenceList><ReferenceList><Reference><Citation>N Engl J Med. 2003 May 15;348(20):1953-66</Citation><ArticleIdList><ArticleId 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uniqKey="Kakiuchi R" first="Rie" last="Kakiuchi">Rie Kakiuchi</name><name sortKey="Kawasaki, Yuko" sort="Kawasaki, Yuko" uniqKey="Kawasaki Y" first="Yuko" last="Kawasaki">Yuko Kawasaki</name><name sortKey="Kiso, Yoshiaki" sort="Kiso, Yoshiaki" uniqKey="Kiso Y" first="Yoshiaki" last="Kiso">Yoshiaki Kiso</name><name sortKey="Nakada, Kiyohiko" sort="Nakada, Kiyohiko" uniqKey="Nakada K" first="Kiyohiko" last="Nakada">Kiyohiko Nakada</name><name sortKey="Takayama, Kentaro" sort="Takayama, Kentaro" uniqKey="Takayama K" first="Kentaro" last="Takayama">Kentaro Takayama</name><name sortKey="Thanigaimalai, Pillaiyar" sort="Thanigaimalai, Pillaiyar" uniqKey="Thanigaimalai P" first="Pillaiyar" last="Thanigaimalai">Pillaiyar Thanigaimalai</name><name sortKey="Yakushiji, Fumika" sort="Yakushiji, Fumika" uniqKey="Yakushiji F" first="Fumika" last="Yakushiji">Fumika Yakushiji</name><name sortKey="Yamamoto, Takehito" sort="Yamamoto, Takehito" uniqKey="Yamamoto T" first="Takehito" last="Yamamoto">Takehito Yamamoto</name><name sortKey="Yamazaki, Yuri" sort="Yamazaki, Yuri" uniqKey="Yamazaki Y" first="Yuri" last="Yamazaki">Yuri Yamazaki</name></noCountry><country name="Japon"><region name="Région de Kantō"><name sortKey="Konno, Sho" sort="Konno, Sho" uniqKey="Konno S" first="Sho" last="Konno">Sho Konno</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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