This second step appears to be the rate-limiting step of the process, in both cases, corresponding to the enzyme-inhibitor covalent bond formation, with an activation free energy of 13.5 and 15.2 kcal•mol -1 for B3 and B4, respectively. The lower activation free energy of B3, together with a higher stabilization of the final covalent product by 2 kcal•mol -1 , suggest that future designs should be based on the modification over this kind of warhead introduced in B3. Analysis of the QM-MM interaction energies between the different residues of the inhibitor and the residues located in the substrate-binding pockets of M pro confirms the predictions assumed during the design of B3 and B4, and the conclusions from geometrical analysis of the structures optimized at the DFT/MM level.