Screening for inhibitors of main protease in SARS-CoV-2: in silico and in vitro approach avoiding secondary amides

Abstract

In addition to vaccines, antiviral drugs are essential for suppressing COVID-19.Although several inhibitor candidates were reported for SARS-CoV-2 main protease, most are highly polar peptidomimetics with poor oral bioavailability and cell membrane permeability. Here, we conducted structure-based virtual screening and in vitro assays to obtain hit compounds belonging to a new chemical space excluding secondary amides. In total, 180 compounds were subjected to the primary assay at 20 µM, and nine compounds with inhibition rates higher than 5% were obtained. The IC 50 of six compounds was determined in dose-response experiments, with the values on the order of 10 -4 µM. Although nitro groups were enriched in the substructure of the hit compounds, they did not significantly contribute to the binding interaction in 1 the predicted docking poses. Physicochemical properties prediction showed good oral absorption. These new scaffolds are promising candidates for future optimization.