Human DNA repair protein O6 – methylguanine-DNA methyltransferase (MGMT) can provide resistance to alkylating agents by DNA damage reversal. Methylation of genes promoter may play a significant role in carcinogenesis. Hence new approaches need to be considered to enhance the inactivation of this protein in order to overcome the resistance to alkylating agents which are still some of the preferred drugs in cancer chemotherapy. In this work different mathematical models are constructed by using quantum chemical parameters and graph theoretical indices. The models are verified and it is observed that both the parameters are suitable for screening these inhibitors. This study opens the door to the development of a new generation of a MGMT inhibitors.