Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

Wenhao Dai; Bing Zhang; Xia-Ming Jiang; Haixia Su; Jian Li; Yao Zhao; Xiong Xie; Zhenming Jin; Jingjing Peng; Fengjiang Liu; Chunpu Li; You Li; Fang Bai; Haofeng Wang; Xi Cheng; Xiaobo Cen; Shulei Hu; Xiuna Yang; Jiang Wang; Xiang Liu; Gengfu Xiao; Hualiang Jiang; Zihe Rao; Leike Zhang; Yechun Xu; Haitao Yang; Hong Liu

The crystal structure of SARS-CoV-2 M pro in complex with 11b is very similar to that of the 11a complex and shows a similar inhibitor binding mode (Figure 2C, 2D, S3B and S3C) . The difference in binding is probably due to the aryl group of 11b at P2. Compared with the cyclohexyl group in 11a, the aryl group undergoes a significant rotation (Figure 2C) . The side chains of residues His41, Met49, Met165 and Val186 interact with this aryl group through hydrophobic interactions ( Figure 2D ). The side chain of Gln189 stabilizes the aryl group with an additional hydrogen bond ( Figure 2D ). In short, these two crystal structures reveal an identical inhibitory mechanism in that these two compounds occupy the substrate-binding pocket, mimicking the intermediates in the catalytic reaction, which blocks the enzyme activity of SARS-CoV-2 M pro .