Targeting the N-terminal domain of the RNA-binding protein of the SARS-CoV-2 with high affinity natural compounds to abrogate the protein-RNA interaction: a molecular dynamics study

Abstract

The emergence of COVID-19 took the world by shock in December 2019, starting from Wuhan, China and swiftly spreading across the globe. The number of COVID-19 cases continues to rise which is a global burden on the health care system worldwide. Efforts are continuing to come up with a solution either to develop a small molecular inhibitor or vaccine, but still no success. In the fight against SARS-CoV-2, targeting a different protein of the SARS-CoV-2 is the need of the hour to impede and relinquish the current pandemic. Therefore, in this study, computational modelling and simulation approaches are used to target the N-terminal domain of the phosphor-nucleoprotein (RNA binding protein), which is primarily responsible for binding and packing the viral genome to get ribonucleoprotein complex (RNP). Our multi-step drug screening approach shortlisted potential drugs. These top hits were confirmed by re-docking which revealed that the interacting molecules block the key residues i.e. Thr57, His59, Ser105, Arg107, and Arg177 and thus ultimately block the NTD from RNA recognition. Furthermore, the activity of the top four hits was also confirmed by using molecular dynamics simulation and free energy calculation. Our analysis suggests that these top hits possess strong inhibitory properties and should be tested experimentally. In conclusion, we hope these top hits would abrogate the binding of RNA and the NTD of the SARS-CoV-2, which might be helpful to combat COVID-19.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• natural compounds
• docking
• interactions
• molecular dynamics

Acknowledgements

The computations were partially performed at the Center for High-Performance Computing, Shanghai Jiao Tong University. We acknowledge their help.

Authors’ contribution

SK, AK, ZH conceptualized the study. SK, AK did the analysis. SK, AK, ZH, DQW wrote the manuscript, revised, visualization and finalizing the final draft. DQW is an academic supervisor. He supervised the study.

Availability of data and materials

All the data will be provided on reasonable demand.

Disclosure statement

The authors declare no conflict of interest.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Dong-Qing Wei is supported by the grants from the Key Research Area Grant 2016YFA0501703 of the Ministry of Science and Technology of China, the National Natural Science Foundation of China (Contract no. 61832019, 61503244), the Natural Science Foundation of Henan Province (162300410060) and Joint Research Funds for Medical and Engineering and Scientific Research at Shanghai Jiao Tong University (YG2017ZD14).