Proposing lead compounds for the development of SARS-CoV-2 receptor-binding inhibitors

Abstract

The COVID-19 pandemic has had deleterious effects on the world and demands urgent measures to find therapeutic agents to combat the current and related future outbreaks. The entry of SARS-CoV-2 into the host’s cell is facilitated by the interaction between the viral spike receptor-binding domain (sRBD) and the human angiotensin-converting enzyme 2 (hACE2). Although the interface of sRBD involved in the sRBD-hACE2 interaction has been projected as a primary vaccine and drug target, currently no small-molecule drugs have been approved for covid-19 treatment targeting sRBD. Herein structure-based virtual screening and molecular dynamics (MD) simulation strategies were applied to identify novel potential small-molecule binders of the SARS-CoV-2 sRBD from an sRBD-targeted compound library as leads for the development of anti-COVID-19 drugs. The library was initially screened against sRBD by using the GOLD docking program whereby 19 compounds were shortlisted based on docking scores after using a control compound to set the selection cutoff. The stability of each compound in MD simulations was used as a further standard to select four hits namely T4S1820, T4589, E634-1449, and K784-7078. Analyses of simulations data showed that the four compounds remained stably bound to sRBD for ≥ 80 ns with reasonable affinities and interacted with pharmacologically important amino acid residues. The compounds exhibited fair solubility, lipophilicity, and toxicity-propensity characteristics that could be improved through lead optimization regimes. The overall results suggest that the scaffolds of T4S1820, E634-1449, and K784-7078 could serve as seeds for developing potent small-molecule inhibitors of SARS-CoV-2 receptor binding and cell entry.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• SARS-CoV-2
• spike receptor-binding domain
• structure-based virtual screening
• molecular dynamics

Author contributions

Conceptualization: E.A.; Methodology: E.A. and R.A.M.; Software: E.A.; Validation: E.A.; Formal analysis: E.A.; Investigation: E.A. and R.A.M.; Resources: E.A. and R.A.M.; Data curation: E.A. and R.A.M.; Writing-original draft preparation: E.A.; Writing-review and editing: E.A.; Visualization: E.A. and R.A.M.; Supervision: E.A. Both authors have read and approved the final manuscript.

Data availability

All data and sources of databases and three-dimensional structures are included in the manuscript and the supplementary material.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.