Identification of natural inhibitors against Mpro of SARS-CoV-2 by molecular docking, molecular dynamics simulation, and MM/PBSA methods

Abstract

The recent outbreak of SARS-CoV-2 disease, also known as COVID-19, has emerged as a pandemic. The unavailability of specific therapeutic drugs and vaccines urgently demands sincere efforts for drug discovery against COVID-19. The main protease (Mpro) of SARS-CoV-2 is a critical drug target as it plays an essential role in virus replication. Therefore for the identification of potential inhibitors of SARS-CoV-2 Mpro, we applied a structure-based virtual screening approach followed by molecular dynamics (MD) study. A library of 686 phytochemicals was subjected to virtual screening which resulted in 28 phytochemicals based on binding energy. These phytochemicals were further subjected to drug-likeness and toxicity analysis, which resulted in seven drug-like hits. Out of seven, five phytochemicals viz., Mpro-Dehydrtectol (-10.3 kcal/mol), Epsilon-viniferin (-8.6 kcal/mol), Peimisine (-8.6 kcal/mol), Gmelanone (-8.4 kcal/mol), and Isocolumbin (-8.4 kcal/mol) were non-toxic. Consequently, these phytochemicals are subjected to MD, post MD analysis, and MM/PBSA calculations. The results of 100 ns MD simulation, RMSF, SASA, Rg, and MM/PBSA show that Epsilon-viniferin (-29.240 kJ/mol), Mpro-Peimisine (-43.031 kJ/mol) and Gmelanone (-13.093 kJ/mol) form a stable complex with Mpro and could be used as potential inhibitors of SARS-CoV-2 Mpro. However, further investigation of these inhibitors against Mpro receptor of COVID-19 is needed to validate their candidacy for clinical trials.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coronavirus
• Mpro
• COVID-19
• molecular docking
• molecular dynamic simulation

Acknowledgements

The authors are thankful to the Head Department of Botany, Kumaun University, Nainital, for providing the facility, space, and resources for this work. The Authors also acknowledge Rashtriya Uchchattar Shiksha Abhiyan (RUSA), Ministry of Human Resource Development, Government of India, to provide Computational infrastructure to establish the Bioinformatics Centre in Kumaun University, S. S. J Campus, Almora.

Disclosure statement

The authors declare that there is no competing interest in this work.

Author contributions

Priyanka Sharma, Sushma Tamta, and Subhash Chandra designed the protocol, conducted experiments, collected data, and prepared the manuscript. Priyanka Sharma and Tushar Joshi help to analyze MD and post-MD simulation. Shalini Mathpal contributed to the construction and analysis of Ligplots. Hemlata Pundir and Tanuja Joshi collaborated in data collection for pharmacokinetic evaluation in the present study. Dr. Subhash Chandra guided in conducting the experiment and reviewing of the manuscript.