Accelerating the discovery of the beyond rule of five compounds that have high affinities toward SARS-CoV-2 spike RBD

Abstract

The battle against SARS-CoV-2 coronavirus is the focal point for the global pandemic that has affected millions of lives worldwide. The need for effective and selective therapeutics for the treatment of the disease caused by SARS-CoV-2 is critical. Herein, we performed a hierarchical computational approach incorporating molecular docking studies, molecular dynamics simulations, absolute binding energy calculations, and steered molecular dynamics simulations for the discovery of potential compounds with high affinity towards SARS-CoV-2 spike RBD. By leveraging ZINC15 database, a total of 1282 in-clinical and FDA approved drugs were filtered out from nearly 0.5 million protomers of relatively large compounds (MW > 500, and LogP ≤ 5). Our results depict plausible mechanistic aspects related to the blockage of SARS-CoV-2 spike RBD by the top hits discovered. We found that the most promising candidates, namely, ZINC95628821, ZINC95617623, ZINC3979524, and ZINC261494658, strongly bind to the spike RBD and interfere with the human ACE2 receptor. These findings accelerate the rational design of selective inhibitors targeting the spike RBD protein of SARS-CoV-2.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• COVID-19
• Spike RBD
• MD simulations

Acknowledgements

The authors thank Compute Canada for computer time. R.A.P. is grateful to the Natural Sciences and Engineering Council of Canada (NSERC) for financial support. A.A.A thanks the School of Graduate Studies of Memorial University for funding.

Author’s contributions

A.A.A. conceptualized the project and was the primary contributor to writing the manuscript. R.A.P. and A.Y. revised the manuscript and provided feedback. All authors reviewed the manuscript.

Disclosure statement

The authors declare no competing interests.

Data availability statement

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

Additional information

Funding

A.Y. thanks Science and Engineering Research Board, New Delhi for research grant number EMR/2016/000769. A.Y is also grateful to Shastri Indo Canadian Institute, New Delhi for Shastri Scholar Travel Subsidy Grant in the year 2016.