In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain).
Identifieur interne : 000296 ( PubMed/Corpus ); précédent : 000295; suivant : 000297In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain).
Auteurs : Phulen Sarma ; Nishant Sekhar ; Manisha Prajapat ; Pramod Avti ; Hardeep Kaur ; Subodh Kumar ; Sanjay Singh ; Harish Kumar ; Ajay Prakash ; Deba Prasad Dhibar ; Bikash MedhiSource :
- Journal of biomolecular structure & dynamics [ 1538-0254 ] ; 2020.
Abstract
The N terminal domain (NTD) of Nucleocapsid protein (N protein) of coronavirus (CoV) binds to the viral (+) sense RNA and results in CoV ribonucleoprotien (CoV RNP) complex, essential for the virus replication. In this study, the RNA-binding N terminal domain (NTD) of the N protein was targeted for the identification of possible inhibitors of RNA binding. Two NTD structures of N proteins were selected (2OFZ and 1SSK, 92% homology) for virtual screening of 56,079 compounds from Asinex and Maybridge library to identify top 15 hits for each of the targets based on "docking score". These top-hits were further screened for MM-GBSA binding free energy, pharmacokinetic properties (QikProp) and drug-likeness (SwissADME) and subjected to molecular dynamics (MD) studies. Two suitable binders (ZINC00003118440 and ZINC0000146942) against the target 2OFZ were identified. ZINC00003118440 is a theophylline derivative under the drug class 'bronchodilEtors' and further screening with approved bronchodilators was also studied to identify their ability to bind to the RNA binding region on the N protein. The other identified top hit is ZINC0000146942, which is a 3,4dihydropyrimidone class molecule. Hence this study suggests two important class of compounds, theophylline and pyrimidone derivaties as possible inhibitors of RNA binding to the N terminal domain of N protein of coronavirus, thus opening new avenues for in vitro validations.
DOI: 10.1080/07391102.2020.1753580
PubMed: 32266867
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Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Avti, Pramod" sort="Avti, Pramod" uniqKey="Avti P" first="Pramod" last="Avti">Pramod Avti</name><affiliation><nlm:affiliation>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Kaur, Hardeep" sort="Kaur, Hardeep" uniqKey="Kaur H" first="Hardeep" last="Kaur">Hardeep Kaur</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Kumar, Subodh" sort="Kumar, Subodh" uniqKey="Kumar S" first="Subodh" last="Kumar">Subodh Kumar</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Singh, Sanjay" sort="Singh, Sanjay" uniqKey="Singh S" first="Sanjay" last="Singh">Sanjay Singh</name><affiliation><nlm:affiliation>Biomedical Informatics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Kumar, Harish" sort="Kumar, Harish" uniqKey="Kumar H" first="Harish" last="Kumar">Harish Kumar</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Prakash, Ajay" sort="Prakash, Ajay" uniqKey="Prakash A" first="Ajay" last="Prakash">Ajay Prakash</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Dhibar, Deba Prasad" sort="Dhibar, Deba Prasad" uniqKey="Dhibar D" first="Deba Prasad" last="Dhibar">Deba Prasad Dhibar</name><affiliation><nlm:affiliation>Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.</nlm:affiliation></affiliation></author><author><name sortKey="Medhi, Bikash" sort="Medhi, Bikash" uniqKey="Medhi B" first="Bikash" last="Medhi">Bikash Medhi</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32266867</idno><idno type="pmid">32266867</idno><idno type="doi">10.1080/07391102.2020.1753580</idno><idno type="wicri:Area/PubMed/Corpus">000296</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" 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Prajapat</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Avti, Pramod" sort="Avti, Pramod" uniqKey="Avti P" first="Pramod" last="Avti">Pramod Avti</name><affiliation><nlm:affiliation>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Kaur, Hardeep" sort="Kaur, Hardeep" uniqKey="Kaur H" first="Hardeep" last="Kaur">Hardeep Kaur</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Kumar, Subodh" sort="Kumar, Subodh" uniqKey="Kumar S" first="Subodh" last="Kumar">Subodh Kumar</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Singh, Sanjay" sort="Singh, Sanjay" uniqKey="Singh S" first="Sanjay" last="Singh">Sanjay Singh</name><affiliation><nlm:affiliation>Biomedical Informatics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Kumar, Harish" sort="Kumar, Harish" uniqKey="Kumar H" first="Harish" last="Kumar">Harish Kumar</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Prakash, Ajay" sort="Prakash, Ajay" uniqKey="Prakash A" first="Ajay" last="Prakash">Ajay Prakash</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author><author><name sortKey="Dhibar, Deba Prasad" sort="Dhibar, Deba Prasad" uniqKey="Dhibar D" first="Deba Prasad" last="Dhibar">Deba Prasad Dhibar</name><affiliation><nlm:affiliation>Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.</nlm:affiliation></affiliation></author><author><name sortKey="Medhi, Bikash" sort="Medhi, Bikash" uniqKey="Medhi B" first="Bikash" last="Medhi">Bikash Medhi</name><affiliation><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Journal of biomolecular structure & dynamics</title><idno type="eISSN">1538-0254</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The N terminal domain (NTD) of Nucleocapsid protein (N protein) of coronavirus (CoV) binds to the viral (+) sense RNA and results in CoV ribonucleoprotien (CoV RNP) complex, essential for the virus replication. In this study, the RNA-binding N terminal domain (NTD) of the N protein was targeted for the identification of possible inhibitors of RNA binding. Two NTD structures of N proteins were selected (2OFZ and 1SSK, 92% homology) for virtual screening of 56,079 compounds from Asinex and Maybridge library to identify top 15 hits for each of the targets based on "docking score". These top-hits were further screened for MM-GBSA binding free energy, pharmacokinetic properties (QikProp) and drug-likeness (SwissADME) and subjected to molecular dynamics (MD) studies. Two suitable binders (ZINC00003118440 and ZINC0000146942) against the target 2OFZ were identified. ZINC00003118440 is a theophylline derivative under the drug class 'bronchodilEtors' and further screening with approved bronchodilators was also studied to identify their ability to bind to the RNA binding region on the N protein. The other identified top hit is ZINC0000146942, which is a 3,4dihydropyrimidone class molecule. Hence this study suggests two important class of compounds, theophylline and pyrimidone derivaties as possible inhibitors of RNA binding to the N terminal domain of N protein of coronavirus, thus opening new avenues for in vitro validations.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32266867</PMID><DateRevised><Year>2020</Year><Month>04</Month><Day>08</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1538-0254</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Apr</Month><Day>08</Day></PubDate></JournalIssue><Title>Journal of biomolecular structure & dynamics</Title><ISOAbbreviation>J. Biomol. Struct. Dyn.</ISOAbbreviation></Journal><ArticleTitle>In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain).</ArticleTitle><Pagination><MedlinePgn>1-11</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1080/07391102.2020.1753580</ELocationID><Abstract><AbstractText>The N terminal domain (NTD) of Nucleocapsid protein (N protein) of coronavirus (CoV) binds to the viral (+) sense RNA and results in CoV ribonucleoprotien (CoV RNP) complex, essential for the virus replication. In this study, the RNA-binding N terminal domain (NTD) of the N protein was targeted for the identification of possible inhibitors of RNA binding. Two NTD structures of N proteins were selected (2OFZ and 1SSK, 92% homology) for virtual screening of 56,079 compounds from Asinex and Maybridge library to identify top 15 hits for each of the targets based on "docking score". These top-hits were further screened for MM-GBSA binding free energy, pharmacokinetic properties (QikProp) and drug-likeness (SwissADME) and subjected to molecular dynamics (MD) studies. Two suitable binders (ZINC00003118440 and ZINC0000146942) against the target 2OFZ were identified. ZINC00003118440 is a theophylline derivative under the drug class 'bronchodilEtors' and further screening with approved bronchodilators was also studied to identify their ability to bind to the RNA binding region on the N protein. The other identified top hit is ZINC0000146942, which is a 3,4dihydropyrimidone class molecule. Hence this study suggests two important class of compounds, theophylline and pyrimidone derivaties as possible inhibitors of RNA binding to the N terminal domain of N protein of coronavirus, thus opening new avenues for in vitro validations.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sarma</LastName><ForeName>Phulen</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sekhar</LastName><ForeName>Nishant</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Prajapat</LastName><ForeName>Manisha</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Avti</LastName><ForeName>Pramod</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kaur</LastName><ForeName>Hardeep</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kumar</LastName><ForeName>Subodh</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Singh</LastName><ForeName>Sanjay</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Biomedical Informatics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kumar</LastName><ForeName>Harish</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Prakash</LastName><ForeName>Ajay</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dhibar</LastName><ForeName>Deba Prasad</ForeName><Initials>DP</Initials><AffiliationInfo><Affiliation>Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Medhi</LastName><ForeName>Bikash</ForeName><Initials>B</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4017-641X</Identifier><AffiliationInfo><Affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>04</Month><Day>08</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Biomol Struct Dyn</MedlineTA><NlmUniqueID>8404176</NlmUniqueID><ISSNLinking>0739-1102</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">2019 novel corona virus</Keyword><Keyword MajorTopicYN="N">2019-nCoV</Keyword><Keyword MajorTopicYN="N">N terminal domain</Keyword><Keyword MajorTopicYN="N">Nucleocapsid protein</Keyword><Keyword MajorTopicYN="N">RNA binding</Keyword><Keyword MajorTopicYN="N">SARS-CoV-2</Keyword><Keyword MajorTopicYN="N">drug design</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>4</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>4</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>4</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32266867</ArticleId><ArticleId IdType="doi">10.1080/07391102.2020.1753580</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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