Pharmacophore based virtual screening, molecular docking, molecular dynamics and MM-GBSA approach for identification of prospective SARS-CoV-2 inhibitor from natural product databases

Abstract

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily appeared in Wuhan, China, in December 2019. At present, no proper therapy and vaccinations are available for the disease, and it is increasing day by day with a high mortality rate. Pharmacophore based virtual screening of the selected natural product databases followed by Glide molecular docking and dynamics studies against SARS-CoV-2 main protease was investigated to identify potential ligands that may act as inhibitors. The molecules SN00293542 and SN00382835 revealed the highest docking score of −14.57 and −12.42 kcal/mol, respectively, when compared with the co-crystal ligands of PDB-6Y2F (O6K) and 6W63 (X77) of the SARS-CoV-2 M^pro. To further validate the interactions of top scored molecules SN00293542 and SN00382835, molecular dynamics study of 100 ns was carried out. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post-MM-GBSA analysis of molecular dynamics data showed free binding energy-71.7004 +/− 7.98, −56.81+/− 7.54 kcal/mol, respectively. The computational study identified several ligands that may act as potential inhibitors of SARS-CoV-2 M^pro. The top-ranked molecules SN00293542, and SN00382835 occupied the active site of the target, the main protease like that of the co-crystal ligand. These molecules may emerge as a promising ligands against SARS-CoV-2 and thus needs further detailed investigations.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Covid-19
• main protease
• pharmacophore
• virtual screening
• molecular docking
• molecular dynamics
• MM-GBSA

Acknowledgements

Authors Banoth Karan Kumar, Faheem and Sankaranarayanan Murugesan gratefully acknowledge to the BITS-Pilani, Pilani campus for providing the adequate facilities to do this research. Our special thanks to Dr. Pritesh Bhat, Senior scientist, Schrodinger, LLC, Bangalore.

Authors contribution

Banoth Karan Kumar - Conceptualization, Methodology, Software, Validation, Data curation, writing the original draft. Faheem – Conceptualization, writing, review, editing. Rupal Ojha – Scientific discussion, review. Vijay Kumar Prajapati- Scientific discussion. Aravinda Pai - Scientific discussion. Kondapalli Venkata Gowri Chandra Sekhar – Discussion, review, editing. Murugesan Sankaranarayanan – Supervision, Project administration, Funding acquisition, review and editing.

Disclosure statement

The authors have no conflicts of interest to declare.

Additional information

Funding

Authors Banoth Karan Kumar, Faheem and Sankaranarayanan Murugesan gratefully acknowledge to the Department of Biotechnology, Indo-Spain, New Delhi. (Ref. No: BT/IN/Spain/39/SM/2017-2018). Additionally, Banoth Karan Kumar thankful to the Ministry of Tribal affairs, Government of India for providing financial assistance (Award no- 201920-NFST-TEL-01497).