Dual inhibition of SARS-CoV-2 spike and main protease through a repurposed drug, rutin

Abstract

The global health emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to alarming numbers of fatalities across the world. So far the researchers worldwide have not been able to discover a breakthrough in the form of a potent drug or an effective vaccine. Therefore, it is imperative to discover drugs to curb the ongoing menace. In silico approaches using FDA approved drugs can expedite the drug discovery process by providing leads that can be pursued. In this report, two drug targets, namely the spike protein and main protease, belonging to structural and non-structural class of proteins respectively, were utilized to carry out drug repurposing based screening. The exposed nature of the spike protein on the viral surface along with its instrumental role in host infection and the involvement of main protease in processing of polyproteins along with no human homologue make these proteins attractive drug targets. Interestingly, the screening identified a common high efficiency binding molecule named rutin. Further, molecular dynamics simulations in explicit solvent affirmed the stable and sturdy binding of rutin with these proteins. The decreased R_g value (4 nm for spike-rutin and 2.23 nm for main protease-rutin) and stagnant SASA analysis (485 nm/S²/N in spike-rutin and 152 nm/S2/N in main protease-rutin) for protein surface and its orientation in the exposed and buried regions suggests a strong binding interaction of the drug. Further, cluster analysis and secondary structure analysis of complex trajectories validated the conformational changes due to binding of rutin.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• spike protein
• main protease
• drug repurposing
• MD simulation
• rutin

Acknowledgements

AK is grateful to Jawaharlal Nehru University and Teri School of Advanced Studies for the management and other facilities. AK is contended to Indian Council of Medical Research (ICMR), India for the SRF position.

Disclosure statement

The authors declare no conflicting interests.

Additional information

Funding

VSR is thankful to Dept. of Health Research (Govt. of India) for the young scientist fellowship (No. 12014/13/2018-HR/E-Office: 3151268). AG is thankful to University Grant Commission, India for the faculty Recharge position.