Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

Abstract

The exponential increase in cases and mortality of coronavirus disease (COVID-19) has called for a need to develop drugs to treat this infection. Using in silico and molecular docking approaches, this study investigated the inhibitory effects of Pradimicin A, Lamivudine, Plerixafor and Lopinavir against SARS-CoV-2 M^pro. ADME/Tox of the ligands, pharmacophore hypothesis of the co-crystalized ligand and the receptor, and docking studies were carried out on different modules of Schrodinger (2019-4) Maestro v12.2. Among the ligands subjected to ADME/Tox by QikProp, Lamivudine demonstrated drug-like physico-chemical properties. A total of five pharmacophore binding sites (A3, A4, R9, R10, and R11) were predicted from the co-crystalized ligand and the binding cavity of the SARS-CoV-2 M^pro. The docking result showed that Lopinavir and Lamivudine bind with a higher affinity and lower free energy than the standard ligand having a glide score of −9.2 kcal/mol and −5.3 kcal/mol, respectively. Plerixafor and Pradimicin A have a glide score of −3.7 kcal/mol and −2.4 kcal/mol, respectively, which is lower than the co-crystallized ligand with a glide score of −5.3 kcal/mol. Molecular dynamics confirmed that the ligands maintained their interaction with the protein with lower RMSD fluctuations over the trajectory period of 100 nsecs and that GLU166 residue is pivotal for binding. On the whole, present study specifies the repurposing aptitude of these molecules as inhibitors of SARS-CoV-2 M^pro with higher binding scores and forms energetically stable complexes with M^pro.

Communicated by Ramaswamy H. Sarma

Keywords:

• Protease inhibitor
• SARS-CoV-2
• COVID-19
• lamivudine
• lopinavir
• docking
• Mpro

Acknowledgements

We would like to acknowledge the National Integrated Cyberinfrastructure system, Center for High Performance Computing (CHPC), Department of Science and Technology, Republic of South Africa for the license to the Lengau cluster and other modules under the Schrodinger suit. Additionally, we appreciate Dr. Samuel Egieyeh, Department of Pharmacy, University of the Western Cape for the time and guidance he invested in this paper to validate its accuracy.

Authors’ contributions

All authors have made significant contributions to the submission of the article. A.O.F, R.T.A, and N.R.S.S conceived the concept and the design of the study, A.K, A.M, and M.M supervised and provided the necessary supports and software required for analysis. The analysis and data interpretations were done collaboratively by all the authors while AOF, RTA, and NRSS prepared the initial draft and also substantially revised the manuscript. A.K, A.M, and M.M thoroughly revised the manuscript. Finally, all authors read and approved the submitted version of the manuscript for publication.

Disclosure statement

The authors declare no competing interests.

Funding

This is not applicable