Discovery of SARS-CoV-2 Mpro inhibitors through rational design of novel fluorinated 1,3,4-oxadiazole amide derivatives: An in-silico study

The main protease (Mpro) of SARS-CoV-2 is an evolutionarily conserved drug discovery target. The present study mainly focused on chemoinformatics computational methods to investigate the efficacy of our newly designed trifluoromethyl-1,3,4-oxadiazole amide derivatives as SARS-CoV-2 Mpro inhibitors. Drug-likeness ADMET analysis, molecular docking simulation, density functional theory (DFT) and molecular dynamics simulation methods were included. A comprehensive drug-likeness analysis was performed on the 14 newly designed compounds (1a~1n), and these series of small molecules inhibitors showed potential anti-SARS-CoV-2 activity. In order to reveal the mechanism of drug interaction, these novel compounds were classified by structure and molecular docking simulations were performed. The results showed good interactions and identified the key amino acid residue GLY-143. Further DFT analysis using B3LYP-D3BJ functional and 6-311 + + G (d, p) basis set was performed to optimize the optimal configuration of the Mpro inhibitors, and the infrared spectrum of the vibration frequency was analyzed to clearly understand the structure and stability of the drug. These new series of small molecule inhibitors studied in this work will provide the necessary theoretical basis for the synthesis and activity evaluation of novel SARS-CoV-2 Mpro inhibitors.