Discovery of 3-oxo-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin derivatives as SARS-CoV-2 main protease inhibitors through virtual screening and biological evaluation

Abstract

The COVID-19 caused by SARS-CoV-2 has led to a global pandemic that continues to impact societies and economies worldwide. The main protease (M^pro) plays a crucial role in SARS-CoV-2 replication and is an attractive target for anti-SARS-CoV-2 drug discovery. Herein, we report a series of 3-oxo-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin derivatives as non-peptidomimetic inhibitors targeting SARS-CoV-2 M^pro through structure-based virtual screening and biological evaluation. Further similarity search and structure-activity relationship study led to the identification of compound M56-S2 with the enzymatic IC₅₀ value of 4.0 μM. Moreover, the molecular simulation and predicted ADMET properties, indicated that non-peptidomimetic inhibitor M56-S2 might serve as a useful starting point for the further discovery of highly potent inhibitors targeting SARS-CoV-2 M^pro.

Keywords: 3-oxo-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin derivatives; Main protease; Molecular simulation; SARS-CoV-2; Virtual screening.