Strategic analyses to identify key structural features of antiviral/antimalarial compounds for their binding interactions with 3CLpro, PLpro and RdRp of SARS-CoV-2: in silico molecular docking and dynamic simulation studies

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel member of the betacoronavirus family is a single-stranded RNA virus that has spread worldwide prompting the World Health Organization to declare a global pandemic. This creates an alarming situation and generates an urgent need to develop innovative therapeutic agents. In this context, an in silico molecular docking and molecular dynamics (MD) simulation study on the existing 58 antiviral and antimalarial compounds was performed on 3CLpro, PLpro and RdRp SARS-CoV-2 proteins. The antiviral compounds are best fitted in the binding pockets and interact more profoundly with the amino acid residues compared to antimalarial compounds. An HIV protease inhibitor, saquinavir showed a good dock score and binding free energy with varied binding interactions against 3CLpro and PLpro. While, adefovir, a nucleotide HBV DNA polymerase inhibitor exhibited good dock score and binding interactions against RdRp. Although, the antimalarial compounds showed relatively less dock score but were found to be crucial in displaying essential binding interactions with these proteins. The MD simulation runs for 100 ns on 3CLpro–saquinavir, PLpro–saquinavir and RdRp–adefovir complexes using Desmond revealed fairly stable nature of interactions. This study helped in understanding the key interactions of the vital functionalities that provide a concrete base to develop lead molecules effective against SARS-CoV-2.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• 3CLpro
• PLpro
• RdRp
• SARS-CoV-2
• docking
• dynamics

Acknowledgements

AMD, VRP, DKL, VGU, SCK thanks Dr. S. J. Surana, Principal, R.C.P.I.P.E.R, Shirpur for providing research facilities. NDA thank the management of Nagar Yuwak Shikshan Sanstha, Nagpur for the kind support. BAB thank Dr. S. Gurumadhva Rao, President, RAKMHSU and Dr. Padma G.M. Rao, Dean, RAKCOPS for their encouragement and support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contribution

Saurabh C. Khadse: Conceptualization, Methodology, Investigation and Interpretation, Writing-original draft, Writing-review and editing. Nikhil D. Amnerkar: Methodology, Editing-original draft, Writing-review and editing, Validation. Ashish M. Dhote: Methodology, Docking studies, Data collection and analysis. Vikas R. Patil: Docking studies, Data collection and analysis. Deepak K. Lokwani: Methodology, MD simulation studies, Interpretation. Vinod G. Ugale: Visualization, Validation, Resources. Nitin B. Charbe: Visualization, Validation, Resources. Bhoomendra A. Bhongade: Critical revision, Editing, Validation.