Molecular docking and simulation studies of synthetic protease inhibitors against COVID-19: a computational study

Abstract

COVID-19 is the most recent threat to global health. Many people preferred treatment in case of infection instead of vaccination. The inhibition of viral replication is a good strategy for the treatment of COVID-19 infection. 3CLpro and PLpro are two important viral proteases responsible for proteolysis, infection, and replication of the virus. Therefore, targeting of these two enzymes is an attractive way to deal with COVID-19. The aim of this study was to screen some synthetic protease inhibitors to determine an appropriate hit molecule against COVID-19 using molecular docking and molecular dynamic simulations. The strategy depends on docking existing synthetic compounds mostly HIV protease inhibitors against two COVID-19 proteases to identify promising drugs for the treatment of COVID-19. We used protein data bank to obtain the X-ray crystal structure of the most important COVID-19 proteases 3CL pro (PDB ID: 6M2N) and PL pro (PDB ID: 6WX4). In this conceptual context, an attempt has been made to suggest an in silico computational relationship between 50 synthetic protease inhibitors and COVID-19 proteases. Out of 50 screened compounds, the best docking scores were found for these five protease inhibitors BDBM7021, BDBM698, BDBM694, BDBM93239, BDBM700. A 100-ns MD simulation was carried out to assess the stability of COVID-19 proteases and inhibitors, revealing an average RMSD value of 0.7 and favorable binding free energy (MM-GBSA) for all complexes confirming their potency as powerful binders in the COVID-19 proteases’ binding pocket. Furthermore, the current results must be confirmed using in-vitro and in-vivo antiviral methods.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• molecular docking
• protease inhibitors
• 3CLpro
• PLpro
• 6M2N
• 6WX4

Acknowledgements

The authors are most thankful for the National Research Centre that has provided support, training, and knowledge. This paper and the research behind it would not have been possible without the exceptional chances for learning, training, and self-development. I would like to express my sincere gratitude to my advisors’ professors and researchers of the Medical Biochemistry Department, National Research Centre for their continuous support, motivation, and immense knowledge.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The docking structures are available upon request from the corresponding author.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.