Synthesis, molecular docking, and binding Gibbs free energy calculation of β-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease

https://doi.org/10.1016/j.molstruc.2023.135409Get rights and content

Highlights

  • A class of β-nitrostyrene derivatives was found to inhibit SARS-CoV-2 3CL protease.

  • Molecular docking shows the key role of Pi-Pi interaction between HIS41 and ligand.

  • The binding free energy correlates with IC50 basicly.

Abstract

The outbreak of novel coronavirus disease 2019 (COVID-19), caused by the novel coronavirus (SARS-CoV-2), has had a significant impact on human health and the economic development. SARS-CoV-2 3CL protease (3CLpro) is highly conserved and plays a key role in mediating the transcription of virus replication. It is an ideal target for the design and screening of anti-coronavirus drugs. In this work, seven β-nitrostyrene derivatives were synthesized by Henry reaction and β-dehydration reaction, and their inhibitory effects on SARS-CoV-2 3CL protease were identified by enzyme activity inhibition assay in vitro. Among them, 4-nitro-β-nitrostyrene (compound a) showed the lowest IC50 values of 0.7297 µM. To investigate the key groups that determine the activity of β-nitrostyrene derivatives and their interaction mode with the receptor, the molecular docking using the CDOCKER protocol in Discovery Studio 2016 was performed. The results showed that the hydrogen bonds between β-NO2 and receptor GLY-143 and the π-π stacking between the aryl ring of the ligand and the imidazole ring of receptor HIS-41 significantly contributed to the ligand activity. Furthermore, the ligand-receptor absolute binding Gibbs free energies were calculated using the Binding Affinity Tool (BAT.py) to verify its correlation with the activity of β-nitrostyrene 3CLpro inhibitors as a scoring function. The higher correlation(r2=0.6) indicates that the absolute binding Gibbs free energy based on molecular dynamics can be used to predict the activity of new β-nitrostyrene 3CLpro inhibitors. These results provide valuable insights for the functional group-based design, structure optimization and the discovery of high accuracy activity prediction means of anti-COVID-19 lead compounds.

Keywords

SARS-CoV-2
3CLpro inhibitor
β-nitrostyrene derivatives
Molecular docking
Receptor-ligand interaction
Binding Gibbs free energies

Data Availability

  • Data will be made available on request.

Cited by (0)

#

These authors contributed equally to this work.

View Abstract