How Nutlin-3 disrupts the MDM2–p53 interaction: a theoretical investigation

Abstract

The tumor suppressor protein p53 is inhibited while mouse double minute 2 (MDM2) protein binds on its transactivation domain. Overexpression of MDM2 impairs p53 function and are observed in many human tumors. Disruption of MDM2–p53 interaction leads to increased p53 level and restores p53 transcriptional activity. Restoration of p53 activity through inhibiting the interaction between p53 and MDM2 represents a promising approach for cancer therapy. A number of small-molecule p53–MDM2 binding inhibitors have been developed during the past several years. Nutlin-3 has shown a potent and selective small-molecule MDM2 antagonist which has a considerable promise in pre-clinical studies. In this study we investigated theoretically the interaction of Nutlin-3 with MDM2 at atomistic level, and compared to the interaction of p53 with MDM2 to explore the molecular basis of inhibition. In MDM2–p53 model, there are three hydrogen bonding interactions between MDM2 and p53. The lengths of the hydrogen bonds are found to be 2.45, 2.46, and 1.89 A whereas interaction energies are −3.82, −3.76, and −5.32 kcal/mol, respectively. The sum of three hydrogen bonding energy is −12.90 kcal/mol. On the other hand, in MDM2–Nutlin-3 model there are four hydrogen bond interactions between MDM2 and Nutlin-3. The bond lengths are found to be 2.29, 1.77, 2.48, and 2.39 A whereas interaction energies are −4.21, −6.63, −3.65, and −3.63 kcal/mol, respectively. The sum of three hydrogen bonding energy is −18.12 kcal/mol. From the comparison between two models, it is revealed that MDM2–Nutlin3 model has four hydrogen bonds whereas MDM2–p53 model has three hydrogen bonds. The interaction energy in MDM2–Nutlin-3 is relatively more stable than MDM2–p53 interaction. Due to stronger hydrogen bond interaction with higher interaction energy, Nutlin-3 blocks the p53-binding pocket of MDM2 and thus disrupts the MDM2–p53 interaction and helps to activate p53 pathway of apoptosis.