SARS-CoV-2 M^pro inhibitors: identification of anti-SARS-CoV-2 M^pro compounds from FDA approved drugs

Abstract

Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (M^pro), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 M^pro using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >−7 kcal/mol. The top 10 screened potential compounds against SARS-CoV-2 M^pro were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability via 100 ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 M^pro revealed R428 (−10.5 kcal/mol), Teniposide (−9.8 kcal/mol), VS-5584 (−9.4 kcal/mol), and Setileuton (−8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• drug repurposing
• structure-based virtual screening
• molecular docking
• molecular dynamics simulation

Acknowledgments

Authors are highly thankful to Dr. Amaresh Kumar Sahoo, Indian Institute of Information Technology, Prayagraj, India for providing his kind support in binding free energy calculation using Prime MMGBSA module of Schrodinger Suite 2019.2.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

This stu

dy was supported by The Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, Saudi Arabia, under grant no. FP-3-42.