Arjunetin as a promising drug candidate against SARS-CoV-2: molecular dynamics simulation studies

Abstract

Stem and bark of the tree Terminalia arjuna Wight & Arn. (Combretaceae) has been documented to exhibit therapeutic properties like cardiotonic, anticancer, antiviral, antibacterial, antifungal, hypercholesterolemia, hypolipidemic, and anti-coagulant. Our previous studies have shown that, ethanolic extract of T. arjuna bark exhibits radical scavenging anti-oxidant activity and also effectively inhibited catalase activity. In this study, oleanane triterpenoids type compounds viz., oleanolic acid, arjunolic acid, arjunolitin, arjunetin were isolated from ethanolic bark extract as bio-active compound and their structures were elucidated using ¹H, ¹³C NMR, HR-ESIMS, IR. Of the various compounds, Arjunetin showed significant inhibition of catalase activity as compared to the other compounds. Based on the structural similarity between arjunetin and current antiviral drugs, we propose that arjunetin might exhibit antiviral activity. Molecular docking and molecular dynamics studies showed that arjunetin binds to the binds to key targets of SARS-CoV-2 namely, 3CLpro, PLpro, and RdRp) with a higher binding energy values (3CLpro, −8.4 kcal/mol; PLpro, −7.6 kcal/mol and RdRp, −8.1 kcal/mol) as compared with FDA approved protease inhibitor drugs to Lopinavir (3CLpro, −7.2 kcal/mole and PLpro −7.7 kcal/mole) and Remdesivir (RdRp −7.6 kcal/mole). To further investigate this, we performed 200–500 ns molecular dynamics simulation studies. The results transpired that the binding affinity of Arjunetin is higher than Remdesivir in the RNA binding cavity of RdRp. Based on structural similarity between arjunetin and Saikosaponin (a known antiviral agents) and based on our molecular docking and molecular dynamic simulation studies, we propose that arjunetin can be a promising drug candidate against Covid-19.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Terminalia arjuna
• catalase inhibition
• SARS-CoV-2 protease
• arjunetin
• molecular docking
• molecular dynamic simulations

Acknowledgments

The authors gratefully acknowledge Dr. Sreevidya Narasimhan, CDRI, Lucknow. The authors wish to thank the SAIF, Department of Chemistry, IIT Madras for EPR, FT-IR, NMR, ESIMS facility and Prof. Pradeepkumar Department of Chemistry, IIT Bombay, for helpful discussion.

Disclosure statement

The authors declare that they have no conflict of financial interest.

Additional information

Funding

Prof. GSN acknowledges Industrial Consultancy and Sponsored Research, IIT Madras for providing exploratory research grant. Prof. GR would like to thank DST and SERB for funding (CRG/2018/000430; DST/SJF/CSA-03/2018-10; SB/SJF/2019-20/12).