Virtual screening and molecular simulation study of natural products database for lead identification of novel coronavirus main protease inhibitors

Abstract

3CL like protease (3CLpro or Mpro) is one of the main proteases of 2019-nCoV. The 3CLpro is a nonstructural protein of SARS-CoV and has an essential role in viral replication and transcription, thus, could be a potential target for anti-SARS drug development. The present study employed ligand- and structure-based approaches to identify the potent inhibitors of 2019-nCoV protease. The e-pharmacophore developed from 3CLpro-1 yielded virtual hits, that were subjected through drug likeliness and PAINS filters to remove interfering compounds. Further comprehensive docking studies, free energy calculations and ADMET studies resulted in two virtual leads- MolPort-000-410-348 and MolPort-002-530-156. The compounds MolPort-000-410-348 and MolPort-002-530-156 displayed good docking score of −12.09 and −13.38 Kcal/mol and free binding energy of −63.34 ± 2.03 and −61.52 ± 2.24 Kcal/mol, respectively. The compounds also exhibited satisfactory predicted ADMET profile and were subjected to molecular dynamic (MD) studies. The MD simulation produced stable complexes of these ligands with 3CLpro protein and ligand RMSD in acceptable limits.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• natural products
• virtual screening
• molecular docking
• protease inhibitors

Acknowledgements

The authors would like to thank MolPort for providing access to their natural compound database. NT, BG, NB and BS are grateful to IIT (BHU), Varanasi for providing teaching assistantship. The authors would also like to extend their gratitude toward Professor David A. Case, Department of Chemistry & Chemical Biology, Rutgers University, New Jersey, USA, for granting a license for Amber 20.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors acknowledge financial support of Seed Research Grant from the IIT (BHU).