Computational investigation on the molecular interactions between MDM2 and its photoactivatable inhibitor

Abstract

The Murine Double Minute 2 (MDM2) protein is a crucial negative regulator of the tumor suppressor p53 molecule. In order to restrict p53 functioning, MDM2 molecules are overproduced in many human tumors. Thus, reactivating p53 in cancer cells using inhibitors, disrupting p53-MDM2 binding, can offer an effective approach for cancer therapy. Recently a photoactivatable MDM2 inhibitor, a photoremovable-protecting group (PPG) in complex with idasanutlin has been reported to exert no functional effect on cellular outgrowth but allows for the selective, non-invasive activation of antitumor properties due to the release of active inhibitor idasanutlin from the complex upon irradiation with 400 nm light. In this study, using molecular docking and Molecular Dynamics (MD) simulations, we have investigated the interaction of (i) PPG-idasanutlin complex and (ii) the active inhibitor idasanutlin with MDM2 at the molecular level. We noticed that the PPG-idasanutlin complex fails to fit into the binding cavity of MDM2. But the active inhibitor idasanutlin when it is free from PPG was found to fit perfectly into the binding cavity of MDM2. From the Dictionary of Secondary Structure of Proteins (DSSP) analysis, we found that the number of α-helices, which aid in the stability of protein, were found to be more in the MDM2-idasanutlin complex rather than in the MDM2-PPG-idasanutlin complex. Using the PDBsum server, we have compared the interaction profiles of MDM2-PPG-idasanutlin, MDM2-idasnautlin and MDM2-p53 complexes. From the interaction profile, we found the active inhibitor, idasanutlin free from PPG to bind to the region in MDM2 where p53 prefers to bind.. Our findings from this study would shed light on designing more potent photoactivatable MDM2 inhibitors.