In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain).
Identifieur interne : 000558 ( 2020/Analysis ); précédent : 000557; suivant : 000559In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain).
Auteurs : Phulen Sarma [Inde] ; Nishant Sekhar [Inde] ; Manisha Prajapat [Inde] ; Pramod Avti [Inde] ; Hardeep Kaur [Inde] ; Subodh Kumar [Inde] ; Sanjay Singh [Inde] ; Harish Kumar [Inde] ; Ajay Prakash [Inde] ; Deba Prasad Dhibar [Inde] ; Bikash Medhi [Inde]Source :
- 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
Affiliations:
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Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Sekhar, Nishant" sort="Sekhar, Nishant" uniqKey="Sekhar N" first="Nishant" last="Sekhar">Nishant Sekhar</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Prajapat, Manisha" sort="Prajapat, Manisha" uniqKey="Prajapat M" first="Manisha" last="Prajapat">Manisha Prajapat</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Avti, Pramod" sort="Avti, Pramod" uniqKey="Avti P" first="Pramod" last="Avti">Pramod Avti</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Kaur, Hardeep" sort="Kaur, Hardeep" uniqKey="Kaur H" first="Hardeep" last="Kaur">Hardeep Kaur</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Kumar, Subodh" sort="Kumar, Subodh" uniqKey="Kumar S" first="Subodh" last="Kumar">Subodh Kumar</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Singh, Sanjay" sort="Singh, Sanjay" uniqKey="Singh S" first="Sanjay" last="Singh">Sanjay Singh</name><affiliation wicri:level="1"><nlm:affiliation>Biomedical Informatics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Biomedical Informatics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Kumar, Harish" sort="Kumar, Harish" uniqKey="Kumar H" first="Harish" last="Kumar">Harish Kumar</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Prakash, Ajay" sort="Prakash, Ajay" uniqKey="Prakash A" first="Ajay" last="Prakash">Ajay Prakash</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></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 wicri:level="1"><nlm:affiliation>Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></affiliation></author><author><name sortKey="Medhi, Bikash" sort="Medhi, Bikash" uniqKey="Medhi B" first="Bikash" last="Medhi">Bikash Medhi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh</wicri:regionArea><wicri:noRegion>Chandigarh</wicri:noRegion></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><affiliations><list><country><li>Inde</li></country></list><tree><country name="Inde"><noRegion><name sortKey="Sarma, Phulen" sort="Sarma, Phulen" uniqKey="Sarma P" first="Phulen" last="Sarma">Phulen Sarma</name></noRegion><name sortKey="Avti, Pramod" sort="Avti, Pramod" uniqKey="Avti P" first="Pramod" last="Avti">Pramod Avti</name><name sortKey="Dhibar, Deba Prasad" sort="Dhibar, Deba Prasad" uniqKey="Dhibar D" first="Deba Prasad" last="Dhibar">Deba Prasad Dhibar</name><name sortKey="Kaur, Hardeep" sort="Kaur, Hardeep" uniqKey="Kaur H" first="Hardeep" last="Kaur">Hardeep Kaur</name><name sortKey="Kumar, Harish" sort="Kumar, Harish" uniqKey="Kumar H" first="Harish" last="Kumar">Harish Kumar</name><name sortKey="Kumar, Subodh" sort="Kumar, Subodh" uniqKey="Kumar S" first="Subodh" last="Kumar">Subodh Kumar</name><name sortKey="Medhi, Bikash" sort="Medhi, Bikash" uniqKey="Medhi B" first="Bikash" last="Medhi">Bikash Medhi</name><name sortKey="Prajapat, Manisha" sort="Prajapat, Manisha" uniqKey="Prajapat M" first="Manisha" last="Prajapat">Manisha Prajapat</name><name sortKey="Prakash, Ajay" sort="Prakash, Ajay" uniqKey="Prakash A" first="Ajay" last="Prakash">Ajay Prakash</name><name sortKey="Sekhar, Nishant" sort="Sekhar, Nishant" uniqKey="Sekhar N" first="Nishant" last="Sekhar">Nishant Sekhar</name><name sortKey="Singh, Sanjay" sort="Singh, Sanjay" uniqKey="Singh S" first="Sanjay" last="Singh">Sanjay Singh</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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