Synthesis, molecular docking, and binding Gibbs free energy calculation of j3-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease

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 pro-tease (3CLpro) is highly conserved and plays a key role in mediating the transcription of virus repli-cation. It is an ideal target for the design and screening of anti-coronavirus drugs. In this work, seven j3-nitrostyrene derivatives were synthesized by Henry reaction and j3-dehydration reaction, and their in-hibitory effects on SARS-CoV-2 3CL protease were identified by enzyme activity inhibition assay in vitro. Among them, 4-nitro-j3-nitrostyrene (compound a ) showed the lowest IC50 values of 0.7297 mu M. To in-vestigate the key groups that determine the activity of j3-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 j3-NO2 and receptor GLY-143 and the pi-pi stacking between the aryl ring of the ligand and the imidazole ring of receptor HIS-41 signif-icantly 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 ac-tivity of j3-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 ac-tivity of new j3-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.(c) 2023 Published by Elsevier B.V.

Automated summary

The outbreak of COVID-19 caused by SARS-CoV-2 has had a significant impact on human health and the economy. In this study, seven β-nitrostyrene derivatives were synthesized and their inhibitory effects on SARS-CoV-2 3CL protease were evaluated. The compound 4-nitro-β-nitrostyrene showed the lowest IC50 value. Molecular docking revealed the important role of hydrogen bonds and π-π stacking interactions in the ligand-binding activity. The correlation between the ligand-receptor binding Gibbs free energy and the activity of β-nitrostyrene 3CL protease inhibitors was also confirmed.