Decoding the Role of MDM2 as a Potential Ubiquitin E3 Ligase and Identifying the Therapeutic Efficiency of Alkaloids against MDM2 in Combating Glioblastoma.

ABSTRACT

Glioblastomas (GBMs) represent the most aggressive form of brain tumor arising from the malignant transformation of astrocytes. Despite various advancements, treatment options remain limited to chemotherapy and radiotherapy followed by surgery giving an overall survival of 14-15 months. These therapies are somewhere restricted in giving a better survival and cure. There is a need for new therapeutics that could potentially target GBM based on molecular pathways and pathology. Here, ubiquitin E3 ligases can be used as targets as they bind a wide array of substrates and therefore can be attractive targets for new inhibitors. Through this study, we have tried to sort various ubiquitin E3 ligases based on their expression, pathways to which these ligases are associated, and mutational frequencies, and then we tried to screen potent inhibitors against the most favorable E3 ligase as very few studies are available concerning inhibition of E3 ligase in GBM. Our study found MDM2 to be the most ideal E3 ligase and further we tried to target MDM2 against various compounds under the alkaloid class. Molecular Docking and MD simulations combined with ADMET properties and BBB scores revealed that only evodiamine and sanguinarine were effective in inhibiting MDM2. We also tried to give a proposed mechanism of how these inhibitors mediate the p53 signaling in GBM. Therefore, the new scaffolds predicted by the computational approach could help in designing promising therapeutic agents targeting MDM2 in glioblastoma.