Design and In Silico Study of the Novel Small Molecular MDM2 Inhibitors

Abstract

Protein-protein Interaction (PPIs) plays a central role in many diseased conditions. Therefore to target and to modulate PPIs is an efficient approach for the disease treatment. Cancer is also arising because of Protein-protein interaction. In cancer, the tumor suppressor p53 protein got inhibited by the MDM2 protein. p53 protein regulates the cell cycle and apoptosis. Interaction between the p53-MDM2 proteins is responsible for the inhibition of the p53 function. By this interaction, MDM2 degrades and inhibits the p53 protein. Hence, to target and inhibit the p53-MDM2 interaction for the treatment of cancer is the rational approach. By targeting this interaction with the drugs, we can selectively kill the cancer cells over the normal cells. Recently, p53-MDM2 interaction inhibitor drugs have been reported by many researchers and pharmaceutical companies. And several drugs entered into the clinical trials. In this study, a novel 1,2,4-triazole based molecules were designed as MDM2 inhibitors and performed their in-silico study. We designed the novel compound 01 and Lead 1a. In this work, In silico study of the Lead 1a and reference compounds (Nutlin 3a, RG7112) was carried out. The molecular docking study of the Novel 1,2,4-triazole based lead 1a and reference compounds was carried out. The docking score of the Lead 1a found to be better than Nutlin 3a and close to RG7112. The various possible conformations and binding affinity values were also determined by the docking study. These results indicate the Lead 1a as a potential MDM2 inhibitor and anti-cancer agent.