Identification of potential novel inhibitors against the SARS-CoV-2 spike protein: targeting RBD and ACE2 interaction

Abstract

The SARS-CoV-2, responsible for the COVID-19 pandemic has wrecked devastation throughout the globe. The SARS-CoV-2 spike (S) glycoprotein plays crucial role in virus attachment, fusion, and entry. This study aims to identify inhibitors targeting the receptor binding domain (RBD) of the S protein using computational and experimental techniques. We carried out virtual screening of four datasets against the S-RBD. Six potential candidate inhibitors were selected for experimental evaluation. Here, we provide experimental evidence that the molecules 9‴-MethyllithosperMate, Epimedin A, Pentagalloylglucose, and Theaflavin-3-gallate have a high binding affinity towards SARS-CoV-2 S-RBD. 9‴-MethyllithosperMate with a K_D value of 1.3 nM serves as the best inhibitor, followed by others with K_D values in micromolar range. We performed molecular dynamics simulation to assess the binding stability of these inhibitors. Hence, our study reports novel inhibitors against the SARS-CoV-2 S-RBD and their predicted binding mode also suggest the possibility to interfere with the ACE2 binding.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• spike protein
• inhibitors
• ACE2
• receptor binding domain
• protein–protein interaction

Acknowledgments

The DST-Purse and Centre of excellence in bioinformatics and Bioinformatics Infrastructure Facility founded by DBT Govt of India to NSR is duly acknowledged. PPR and SG thank DST-FIST and DBT-BUILDER for funding the central instrumentation facility and for extending SLS funding. We acknowledge the financial assistance provided by the University Grant Commission in the form of Junior Research Fellowship (JRF) to JV and ICMR fellowship to PPR.

Disclosure statement

The authors declare that there are no conflicts of interest.

Authors’ contributions

The in silico work was designed and carried out by JV and NSR. The in vitro experimental study was designed and performed by PPR and SG. All authors read and approve the final manuscript.

Data availability statement

All data generated or analysed during the study are included in this published article [and its supplementary information files].

Additional information

Funding

The authors declare that no funds or grants were received during the preparation of this manuscript.