In both cases, the interactions between the protein and the inhibitors are dominated by those in the P1:::S1 site, as in our previous studies. Finally, the good overlapping between the structures of either the reactant complex E:I or the final covalent product E-I obtained with the two tested inhibitors and two cocrystal structures of covalent adduct of similar compounds bound to SARS CoV-2 M pro suggest that B3 and B4 can pose in the active site of the protein, and no dramatic geometrical changes occurs in in the protein along the reaction of the inhibition process. The obtained reaction mechanism of B4 with such low energy barrier, suggests that terminal hydroxyl group is likely an important structural element of its inhibitory activity. This would also mean that modulation of the pKa of this group might represent an effective strategy to improve the potency of this specific class of HMKs.