Computational prediction of covalent inhibitor binding affinity presents a unique challenge since the binding process consists of multiple steps, which are not necessarily independent of each other. Despite their high potency, covalent inhibitors often lack selectivity between proteases. In the current study, we investigated α-ketoamide analogs, which covalently bind to catalytic cysteine/serine in a reversible manner, and thus, are less toxic than irreversible binders. The relative binding free energy of α-ketoamides was calculated for both noncovalent and covalent bond state in the two highly homologous isoforms, calpain1 and calpain2.