Targeting MDM2-p53 interaction in Glioblastoma: Transcriptomic analysis and Peptide-Based inhibition strategy

Abstract

MDM2 is a gene that encodes a protein involved in cell survival, growth, and DNA repair. It has been implicated in the development and progression of glioblastoma (GBM). Inhibition of the MDM2-p53 interaction has emerged as a promising strategy for treating GBM. In this study, we performed comprehensive transcriptomic expression analysis from diverse datasets and observed MDM2 overexpression in a subset of GBM cases. MDM2 negatively regulates the major onco-suppressor p53. The interaction between MDM2 and p53 is a promising target for cancer therapy, as it can trigger p53-mediated cell death in response to different stress conditions, such as oncogene activation or DNA damage. In this study, we have identified a peptide-based inhibition of MDM2 as a therapeutic strategy for GBM. We have further validated the stability of the MDM2-peptide interaction using a molecular structural dynamics approach. The major trajectories, including root mean square of deviation (RMSD), root mean square of fluctuation (RMSF), and radius of gyration (RoG), indicate that the candidate peptides have a more stable binding compared to the native ligand and control drug. The stability of the binding interaction was further estimated by MMGBSA analysis, which also suggests that MDM2 has a stable binding with both peptide molecules. Based on these results, peptides P-1843 and P-3837 could be tested further for experimental validation to confirm their targeted inhibition of MDM-2. This approach could provide a highly selective and efficient inhibitor with potentially fewer side effects and less toxicity compared to small drug-based molecules.