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.

由 SARS-CoV-2 引起的 COVID-19 已导致全球大流行，继续影响全世界的社会和经济。主要蛋白酶 (M ^pro ) 在 SARS-CoV-2 复制中发挥着至关重要的作用，是抗 SARS-CoV-2 药物发现的一个有吸引力的靶点。在此，我们通过基于结构的虚拟筛选和生物学研究，报告了一系列 3-oxo-1,2,3,4-四氢吡啶并[1,2- a ]吡嗪衍生物作为针对 SARS-CoV-2 M ^pro的非拟肽抑制剂。评估。进一步的相似性搜索和构效关系研究导致鉴定出化合物M56-S2，其酶促IC ₅₀值为4.0 μM。此外，分子模拟和预测的 ADMET 特性表明，非拟肽抑制剂M56-S2可能作为进一步发现针对 SARS-CoV-2 M ^{pro 的}高效抑制剂的有用起点。