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In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain).

Authors
  • Sarma, Phulen1
  • Shekhar, Nishant1
  • Prajapat, Manisha1
  • Avti, Pramod2
  • Kaur, Hardeep1
  • Kumar, Subodh1
  • Singh, Sanjay3
  • Kumar, Harish1
  • Prakash, Ajay1
  • Dhibar, Deba Prasad4
  • Medhi, Bikash1
  • 1 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. , (India)
  • 2 Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India. , (India)
  • 3 Biomedical Informatics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. , (India)
  • 4 Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India. , (India)
Type
Published Article
Journal
Journal of biomolecular structure & dynamics
Publication Date
May 01, 2021
Volume
39
Issue
8
Pages
2724–2732
Identifiers
DOI: 10.1080/07391102.2020.1753580
PMID: 32266867
Source
Medline
Keywords
Language
English
License
Unknown

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 'bronchodilators' 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. Communicated by Ramaswamy H. Sarma.

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