In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain).
Identifieur interne : 003811 ( Ncbi/Curation ); précédent : 003810; suivant : 003812In-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
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<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>
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