Figure shows a schematic representation of these interactions, Figure reports the average interaction energies (electrostatic plus Lennard-Jones) between M pro residues and inhibitor fragments (see Supporting Information for details). A list of relevant interatomic distances is deposited in the Supporting Information. Analysis of the results confirms the formation of a stable reactant Michaelis complex in both cases, with a similar pattern of interactions. Keeping in mind that the difference between B3 and B4 is restricted to the warhead, and in both cases the interactions with the S1' take place through hydrogen bond interactions with the carbonyl oxygen next to P1 that is common in both inhibitors, the results appear as reasonable. Thus, this carbonyl group is interacting with the oxyanion hole located in S1' formed by G143, S144 and C145. In addition, there are some not direct interactions that also stabilize the P1' fragment, such as L27, N28, G146 and S147. The specific favorable interactions between the lactam ring on P1 and S1 are almost equivalent in both inhibitors, mainly through interactions with P140, N142, H163 and E166. The backbone atoms of the residues of the P2 site are the responsible of the interactions with Q189, H164, D187 and M165. Finally, it is worth mentioning the unfavorable interaction with R40, which is ca. 9 Å from P1, thus corresponding to an electrostatic interaction.