Molecular docking and simulation studies on SARS-CoV-2 M^pro reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19

Abstract

The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30^th January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 M^pro inhibitor by molecular docking and molecular dynamic simulation studies. Drug repurposing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX, http://www.selleckchem.com) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100 ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti-viral drug libraries interact with SARS-CoV-2 M^pro at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynamics simulations of 100 ns revealed the mean RMSD value of 2.25 Å for all the complex systems. This shows that lead compounds bound tightly within the M^pro cavity and thus having conformational stability. Glutamic acid (Glu166) of M^pro is a key residue to hold and form a stable complex of reported lead compounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 M^pro.

GRAPHICAL ABSTRACT

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2 main protease (Mpro)
• drug repurposing
• molecular docking
• molecular dynamic simulation

Acknowledgements

The authors are thankful to Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune for the physical infrastructure and Department of Science and Technology Science and Engineering Research Board (DST-SERB), Govt. of India, New Delhi, (File Number: YSS/2015/002035) for utilizing an Optimized Supercomputer for docking and dynamics calculations. Senior Research Fellowship awarded to Kiran Bharat Lokhande (Project ID: 2019-3458; File No.: ISRM/11(54)/2019) by the Indian Council of Medical Research, New Delhi is also acknowledged. Authors also acknowledge Ms. Shweta Ashok More, Ph.D. Scholar, Y.B. Chavan College of Pharmacy, Aurangabad, India for technical help during MM/GBSA calculation for this study.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

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