The introduced pyridone ring should be compatible with the three-dimensional structure of the target which has a crucial role for effective inhibition. In order to confirm this, the authors solved the crystal structure of Mpro of SARS-CoV-2 at 1.75 Å resolution and found that the crystal structure is highly similar to that of SARS-CoV Mpro only with a 0.53 Å r.m.s difference between the two free enzymes. SARS-CoV-2 Mpro forms a tight dimer and has a contact interface mainly between domain II of molecule A and the NH2-terminal residues of molecule B where this dimerization is important for catalytic activity. Unlike SARS-CoV-2, SARS-CoV Mpro dimer has a polar interaction between the two domains III involving a 2.60 Å hydrogen bond between the side chain hydroxyl groups of Thr285 of each protomer which is also supported by a hydrophobic interaction between the side chain of Ile286 and Thr285. In SARS-CoV-2 Mpro, threonine is replaced with alanine and isoleucine with leucine. As suggested by authors, Alanine replacements change the enzyme dynamics and increase its catalytic activity by allowing the two domains III to be in a close contact; although, the catalytic activity of SARS-CoV-2 Mpro was only slightly higher with similar Kd of dimer dissociation (~2.5 μM).