In this study, the interaction of seven potential inhibitors in complex with SARS-CoV-2 ’ s M protease (M pro) is modelled and optimized using ONIOM (Own N-layered Integrated molecular Orbital and molecular Mechanics; QM/MM) approach . Density functional theory is used for the small system and Universal Force Field is used for the rest of the molecule with ONIOM (m062x/6-311++G (d, p): UFF) model chemistry . The seven inhibitors that are used in this study are N3, ebselen, disulfiram, tideglusib, carmofur, shikonin and PX-12 . The calculated interaction energy between the inhibitor and M proshows a strong inhibition of M proactivity with N3, ebselen as well as PX-12 inhibitors . The two former inhibitors are previously reported as strong inhibitors; however, the strong inhibition effect of PX-12 has not been previously reported . The results of this study can provide useful insight into designing an effective inhibitor drug for SARS-nCoV, suggesting a better inhibition from PX-12 than ebselen.