Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies.
Identifieur interne : 001197 ( PubMed/Checkpoint ); précédent : 001196; suivant : 001198Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies.
Auteurs : Pillaiyar Thanigaimalai [Japon] ; Sho Konno ; Takehito Yamamoto ; Yuji Koiwai ; Akihiro Taguchi ; Kentaro Takayama ; Fumika Yakushiji ; Kenichi Akaji ; Shen-En Chen ; Aurash Naser-Tavakolian ; Arne Schön ; Ernesto Freire ; Yoshio HayashiSource :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2013.
Descripteurs français
- KwdFr :
- Activation enzymatique (), Concentration inhibitrice 50, Conception de médicament, Cysteine endopeptidases (métabolisme), Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Inhibiteurs de protéases (synthèse chimique), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Relation structure-activité, Simulation de docking moléculaire, Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- métabolisme : Cysteine endopeptidases, Protéines virales.
- pharmacologie : Inhibiteurs de protéases.
- synthèse chimique : Inhibiteurs de protéases.
- Activation enzymatique, Concentration inhibitrice 50, Conception de médicament, Inhibiteurs de protéases, Relation structure-activité, Simulation de docking moléculaire.
English descriptors
- KwdEn :
- Cysteine Endopeptidases (metabolism), Drug Design, Enzyme Activation (drug effects), Inhibitory Concentration 50, Molecular Docking Simulation, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), SARS Virus (enzymology), Structure-Activity Relationship, Viral Proteins (antagonists & inhibitors), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Protease Inhibitors.
- chemical , chemistry : Protease Inhibitors.
- chemical , metabolism : Cysteine Endopeptidases, Viral Proteins.
- drug effects : Enzyme Activation.
- enzymology : SARS Virus.
- chemical , pharmacology : Protease Inhibitors.
- Drug Design, Inhibitory Concentration 50, Molecular Docking Simulation, Structure-Activity Relationship.
Abstract
We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
DOI: 10.1016/j.ejmech.2013.07.037
PubMed: 23994330
Affiliations:
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()</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Inhibiteurs de protéases (synthèse chimique)</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Protéines virales (métabolisme)</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</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="chemical synthesis" xml:lang="en"><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines 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Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation enzymatique</term><term>Concentration inhibitrice 50</term><term>Conception de médicament</term><term>Inhibiteurs de protéases</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">23994330</PMID><DateCompleted><Year>2014</Year><Month>08</Month><Day>12</Day></DateCompleted><DateRevised><Year>2020</Year><Month>04</Month><Day>07</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1768-3254</ISSN><JournalIssue CitedMedium="Internet"><Volume>68</Volume><PubDate><Year>2013</Year><Month>Oct</Month></PubDate></JournalIssue><Title>European journal of medicinal chemistry</Title><ISOAbbreviation>Eur J Med Chem</ISOAbbreviation></Journal><ArticleTitle>Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies.</ArticleTitle><Pagination><MedlinePgn>372-84</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ejmech.2013.07.037</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0223-5234(13)00485-6</ELocationID><Abstract><AbstractText>We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.</AbstractText><CopyrightInformation>Copyright © 2013 Elsevier Masson SAS. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Thanigaimalai</LastName><ForeName>Pillaiyar</ForeName><Initials>P</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>Konno</LastName><ForeName>Sho</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Yamamoto</LastName><ForeName>Takehito</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Koiwai</LastName><ForeName>Yuji</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Taguchi</LastName><ForeName>Akihiro</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Takayama</LastName><ForeName>Kentaro</ForeName><Initials>K</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>Chen</LastName><ForeName>Shen-En</ForeName><Initials>SE</Initials></Author><Author ValidYN="Y"><LastName>Naser-Tavakolian</LastName><ForeName>Aurash</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Schön</LastName><ForeName>Arne</ForeName><Initials>A</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><GrantList CompleteYN="Y"><Grant><GrantID>P01 GM056550</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 GM057144</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>GM57144</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>GM56550</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>08</Month><Day>09</Day></ArticleDate></Article><MedlineJournalInfo><Country>France</Country><MedlineTA>Eur J Med Chem</MedlineTA><NlmUniqueID>0420510</NlmUniqueID><ISSNLinking>0223-5234</ISSNLinking></MedlineJournalInfo><ChemicalList><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="D003546" MajorTopicYN="N">Cysteine Endopeptidases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015195" MajorTopicYN="Y">Drug Design</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004789" MajorTopicYN="N">Enzyme Activation</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020128" MajorTopicYN="N">Inhibitory Concentration 50</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D062105" MajorTopicYN="N">Molecular Docking Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011480" MajorTopicYN="Y">Protease Inhibitors</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" 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="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><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Cysteine protease inhibitors</Keyword><Keyword MajorTopicYN="N">Dipeptide</Keyword><Keyword MajorTopicYN="N">Peptidomimetics</Keyword><Keyword MajorTopicYN="N">SARS</Keyword><Keyword MajorTopicYN="N">SARS-CoV 3CL(pro)</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2013</Year><Month>04</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2013</Year><Month>07</Month><Day>17</Day></PubMedPubDate><PubMedPubDate 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Kantō</li></region><settlement><li>Tokyo</li></settlement></list><tree><noCountry><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><name sortKey="Chen, Shen En" sort="Chen, Shen En" uniqKey="Chen S" first="Shen-En" last="Chen">Shen-En Chen</name><name sortKey="Freire, Ernesto" sort="Freire, Ernesto" uniqKey="Freire E" first="Ernesto" last="Freire">Ernesto Freire</name><name sortKey="Hayashi, Yoshio" sort="Hayashi, Yoshio" uniqKey="Hayashi Y" first="Yoshio" last="Hayashi">Yoshio Hayashi</name><name sortKey="Koiwai, Yuji" sort="Koiwai, Yuji" uniqKey="Koiwai Y" first="Yuji" last="Koiwai">Yuji Koiwai</name><name sortKey="Konno, Sho" sort="Konno, Sho" uniqKey="Konno S" first="Sho" last="Konno">Sho Konno</name><name sortKey="Naser Tavakolian, Aurash" sort="Naser Tavakolian, Aurash" uniqKey="Naser Tavakolian A" first="Aurash" last="Naser-Tavakolian">Aurash Naser-Tavakolian</name><name sortKey="Schon, Arne" sort="Schon, Arne" uniqKey="Schon A" first="Arne" last="Schön">Arne Schön</name><name sortKey="Taguchi, Akihiro" sort="Taguchi, Akihiro" uniqKey="Taguchi A" first="Akihiro" last="Taguchi">Akihiro Taguchi</name><name sortKey="Takayama, Kentaro" sort="Takayama, Kentaro" uniqKey="Takayama K" first="Kentaro" last="Takayama">Kentaro Takayama</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></noCountry><country name="Japon"><region name="Région de Kantō"><name sortKey="Thanigaimalai, Pillaiyar" sort="Thanigaimalai, Pillaiyar" uniqKey="Thanigaimalai P" first="Pillaiyar" last="Thanigaimalai">Pillaiyar Thanigaimalai</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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