Virtual screening and dynamics of potential inhibitors targeting RNA binding domain of nucleocapsid phosphoprotein from SARS-CoV-2

Yadav, Rohitash; Imran, Mohammed; Dhamija, Puneet; Suchal, Kapil; Handu, Shailendra

doi:10.1080/07391102.2020.1778536

Cited by 50 publications

(51 citation statements)

References 43 publications

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“…NCp is an essential co-factor in the replication, transcription and packaging of the SARS-COV-2 genome [9][10][11][12][13][14][15][16][17][18][19][20]. Inhibiting the function of NCp is therefore an attractive approach to prevent the transmission, infection and virulence of SARS-COV-2 [21][22][23][24][25][26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Structure Model Analysis Of Phosphorylation Dependent Binding And Sequestration Of SARS-COV-2 Encoded Nucleocapsid Protein By Protein 14-3-3

Limtung

2020

Preprint

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Phosphorylation of serines 197 and 206 of SARS-COV-2 Nucleocapsid protein (NCp) enhanced the stability and binding efficiency and sequestration of NCp to Protein 14-3-3 by increasing the Stability Energy (ΔGstability energy) and Binding Energy (ΔΔGbinding energy) from ~545 Kcal/mol to ~616 Kcal/mol, and from 108 Kcal/mol to ~228 Kcal/mol respectively. The calculated Binding Energy Difference (ΔΔGbinding energy difference) between dephospho-NCp-14-3-3 complex and phospho-NCp-13-3-3 complex was ~72 Kcal/mol. Phosphorylations of serines 186, 197, 202 and 206, and threonines 198 and 205 NCp also caused an increase in the Stability Energy (ΔGstability energy) and Binding Energy (ΔΔGbinding energy) from ~545 Kcal/mol to ~617, 616, 583, 580, 574, 564 and 566 Kcal/mol and from ~108 Kcal/mol to ~228, 216, 184, 188, 184, 174 and 112 Kcal/mol respectively. Phosphorylation of NCp on serines 197 and 206 caused a decrease in Stability Energy and Binding Energy from ~698 Kcal/mol to 688 Kcal/mol, and from ~91 Kcal/mol to ~82 Kcal/mol for the dimerization of NCp. These results support the existence of a phosphorylation dependent cellular mechanism to bind and sequester NCp.

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Section: Discussionmentioning

confidence: 99%

Structure Model Analysis Of Phosphorylation Dependent Binding And Sequestration Of SARS-COV-2 Encoded Nucleocapsid Protein By Protein 14-3-3

Limtung

2020

Preprint

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“…However, unlike 6M3M, 6VYO and 6WKP have been deposited as a complex with two and four other smaller ligands respectively. Furthermore, 6VYO has the lowest R-factor of about 2.05, representing a high quality structure 47,48 , and thus may be preferred during molecular docking and molecular dynamics simulations studies 40,41,49 .…”

Section: Rna-binding Domains Of Sars-cov-2 N Proteinsmentioning

confidence: 99%

Biophysical analysis of SARS‐CoV‐2 transmission and theranostic development via N protein computational characterization

Sabbih

Korsah

Jeevanandam

et al. 2020

Biotechnology Progress

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Recently, SARS-CoV-2 has been identified as the causative factor of viral infection called Covid-19, that belongs to the zoonotic beta coronavirus family known to cause respiratory disorders or viral pneumonia, followed by an extensive attack on organs that express angiotensin-converting enzyme II (ACE2). Human transmission of this virus occurs via respiratory droplets from symptomatic and asymptomatic patients, that are released into the environment after sneezing or coughing. These droplets are capable of staying in the air as aerosols or surfaces and can be transmitted to persons through inhalation or contact with contaminated surfaces. Thus, there is an urgent need for advanced theranostic solutions to control the spread of Covid-19 infection. The development of such fit-for-purpose technologies hinges on a proper understanding of the transmission, incubation and structural characteristics of the virus in the external environment as well as within the host. Hence, this article describes the development of an intrinsic model to describe the incubation characteristics of the virus under varying environmental factors. It also discusses on the evaluation of SARS-CoV-2 structural nucleocapsid protein properties via computational approaches to generate high-affinity binding probes for effective diagnosis and targeted treatment applications by specific targeting of viruses. In addition, this article provides useful insights on the transmission behavior of the virus and create new opportunities for theranostics development.

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“…The functional polypeptides are produced by the proteolysis of these polyproteins (Krichel et al., 2020 ). The structural proteins are namely Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N; Hasan et al., 2020 ; McBride et al., 2014 ; Yadav et al., 2020 ). The latest SARS CoV-2 virus is a beta virus (Xie & Chen, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Virtual screening, ADMET prediction and dynamics simulation of potential compounds targeting the main protease of SARS-CoV-2

Yadav

Imran

Dhamija

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The coronavirus disease-2019 caused by a novel SARS CoV-2 virus has emerged as a global threat. Still, no drugs are available for its treatment. The main protease is the most conserved structure responsible for the posttranslational processing of non-structural polyproteins of this virus. Therefore, it can be the potential target for drug discovery against SARS CoV-2. Twenty-one thousand two hundred and seven chemical compounds used for sequential virtual screening studies including coronavirus screening compounds (Life Chemical database) and antiviral compounds (Asinex database). The Schrodinger suite 2019 employed for high throughput screening, molecular docking and MM-GBSA through the Glide module. Subsequently, 23 compounds were selected in the phase first selection criteria for re-docking with AutoDock and iDock followed by ADMET prediction. The drug-likeness predicted through Lipinski's rule of five, Veber's rule and Muegge's rule. Finally, three ligands were selected for molecular dynamics simulation studies over 150 ns against the main protease of the SARS CoV-2. They showed promising docking scores on Glide, iDock and AutoDock Vina algorithms (ligand F2679-0163: À10.75, À10.29 and À9.2; ligand F6355-0442: À9.38, À8.61 and À7.6; ligand 8250: À9.795, À7.94 and À7.5), respectively. The RMSD parameter remained stable at 2.5 Å for all the three ligands for 150 ns. The high RMSF fluctuations, RoG of around 22 Å and the binding free energy were favorable in each case. The hydrogen bond interactions of 8250, F6355-0442 and F2679-0163 were six, five and three, respectively. These compounds can be further explored for in vitro experimental validation against SARS-CoV-2.

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Virtual screening and dynamics of potential inhibitors targeting RNA binding domain of nucleocapsid phosphoprotein from SARS-CoV-2

Cited by 50 publications

References 43 publications

Structure Model Analysis Of Phosphorylation Dependent Binding And Sequestration Of SARS-COV-2 Encoded Nucleocapsid Protein By Protein 14-3-3

Structure Model Analysis Of Phosphorylation Dependent Binding And Sequestration Of SARS-COV-2 Encoded Nucleocapsid Protein By Protein 14-3-3

Biophysical analysis of SARS‐CoV‐2 transmission and theranostic development via N protein computational characterization

Virtual screening, ADMET prediction and dynamics simulation of potential compounds targeting the main protease of SARS-CoV-2

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