Development of novel ligands against SARS‐CoV‐2 Mpro enzyme: an in silico and in vitro Study

Background: Despite tremendous efforts made by scientific community during the outbreak of COVID‐19 pandemic, this disease still remains as a public health concern. Although different types of vaccines were globally used to reduce the mortality, emergence of new variants of SARS‐CoV‐2 is a challenging issue in COVID‐19 pharmacotherapy. In this context, target therapy of SARS‐CoV‐2 by small ligands is a promising strategy. Methods: In this investigation, we applied ligand‐based virtual screening for finding novel molecules based on nirmatrelvir structure. Various criteria including drug‐likeness, ADME, and toxicity properties were applied for filtering the compounds. The selected candidate molecules were subjected to molecular docking and dynamics simulation for predicting the binding mode and binding free energy, respectively. Then the molecules were experimentally evaluated in terms of antiviral activity against SARS‐CoV‐2 and toxicity assessment. Results: The results demonstrated that the identified compounds showed inhibitory activity towards SARS‐CoV‐2 Mpro. Conclusion: In summary, the introduced compounds may provide novel scaffold for further structural modification and optimization with improved anti SARS‐CoV‐2 Mpro activity.