Cocrystal structures of 4 bound to the 3CLpro of both SARS CoV-1 and CoV-2 were solved at 1.47 and 1.26 Å resolutions, respectively (PDB codes 6XHL and 6XHM).47 As expected, the ligand binding sites of the main protease from SARS CoV-1 and SARS CoV-2 are conserved in sequence and are nearly identical structurally. The schematic diagram in Figure 5 is representative of the covalent adduct between 4 and the 3CLpro from both CoV-1 and CoV-2. The warhead HMK carbonyl carbon of 4 forms a covalent bond to the 3CLpro active-site cysteine (Cys145) sulfur generating a tetrahedral carbinol complex (1.8 Å C–S bond length). This carbinol hydroxyl forms hydrogen bonds with the backbone NH of Cys145 and with the amide NH of Gly143 via a bridging water molecule. Another key active-site interaction is the hydrogen bond between the primary alcohol moiety of 4 and the catalytic His41. Similar interactions between catalytic His residues and the OH moiety of HMK in other protease–inhibitor complexes have been reported.43