In this study, we performed rigorous absolute binding free energy simulations and ONIOM QM/MM calculations to estimate-from a thermodynamical standpoint-the energetics of binding of some promising reversible covalent inhibitors of the SARS-CoV-2 M pro . The inhibitors studied include 11a, GC373, MI30, and PF-231. These inhibitors contain either an aldehyde or ketone moiety as warhead and form a covalent bond with the active site Cys145 of the M pro . Cys145 is essential for the catalytic activity of the M pro , so modification of this residue by a targeted covalent inhibitor will have deleterious effects on the function of the M pro and the virus as a whole.