Biflavonoids from Rhus succedanea as probable natural inhibitors against SARS-CoV-2: a molecular docking and molecular dynamics approach

Abstract

The recent outbreak of SARS-CoV-2 has quickly become a worldwide pandemic and generated panic threats for both the human population and the global economy. The unavailability of effective vaccines or drugs has enforced researchers to hunt for a potential drug to combat this virus. Plant-derived phytocompounds are of applicable interest in the search for novel drugs. Bioflavonoids from Rhus succedanea are already reported to exert antiviral activity against RNA viruses. SARS-CoV-2 Mpro protease plays a vital role in viral replication and therefore can be considered as a promising target for drug development. A computational approach has been employed to search for promising potent bioflavonoids from Rhus succedanea against SARS-CoV-2 Mpro protease. Binding affinities and binding modes between the biflavonoids and Mpro enzyme suggest that all six biflavonoids exhibit possible interaction with the Mpro catalytic site (−19.47 to −27.04 kcal/mol). However, Amentoflavone (−27.04 kcal/mol) and Agathisflavone (−25.87 kcal/mol) interact strongly with the catalytic residues. Molecular dynamic simulations (100 ns) further revealed that these two biflavonoids complexes with the Mpro enzyme are highly stable and are of less conformational fluctuations. Also, the hydrophobic and hydrophilic surface mapping on the Mpro structure as well as biflavonoids were utilized for the further lead optimization process. Altogether, our findings showed that these natural biflavonoids can be utilized as promising SARS-CoV-2 Mpro inhibitors and thus, the computational approach provides an initial footstep towards experimental studies in in vitro and in vivo, which is necessary for the therapeutic development of novel and safe drugs to control SARS-CoV-2.

Communicated by Ramaswamy H. Sarma

Research highlights

1. Rhus succedanea biflavonoids have antiviral activity.

2. The molecular interactions and molecular dynamics displayed that all six biflavonoids bound with a good affinity to the same catalytic site of Mpro.

3. The compound Amentoflavone has a strong binding affinity (−27.0441 kcal/mol) towards Mpro.

4. The binding site properties of SARS-CoV-2-Mpro can be utilized in a novel discovery and lead optimization of the SARS-CoV-2-Mpro inhibitor.

Keywords:

• Coronavirus
• SARS-CoV-2
• COVID-19
• Mpro protein
• Rhus succedanea
• biflavonoids
• molecular docking
• molecular dynamics simulation

Acknowledgements

The authors are thankful to Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, for providing the necessary facilities and infrastructure to carry out this work. The authors also acknowledge the Department of Science and Technology-Science and Engineering Research Board (DST-SERB), Govt. of India, New Delhi, (File Number: YSS/2015/002035) for Optimized Supercomputer facility for dynamics calculations. Kiran Bharat Lokhande acknowledges the Indian Council of Medical Research (ICMR), New Delhi, for Senior Research Fellowship (Project ID: 2019-3458; File: ISRM/11(54)/2019).

Additional information

Funding

This work received funding from Dr. D. Y. Patil Vidyapeeth, Pune (DPU/421/2018).