Epicatechin an incredible tool to dissociate MDM2-p53 interaction for treatment of glioblastomas: a molecular docking and molecular dynamics simulation approach

Abstract

Glioblastomas, aggressive tumors that arise from malignant transformation of astrocytes, account for 60% brain cancer cases. Current treatments including radiation and chemotherapy accompanied by surgeries result in an average survival increment of 15 months. New therapeutics based on molecular pathology and pathways demonstrate great scope. p53, a tumor-suppressor protein is downregulated by MDM2. In malignant conditions, MDM2 levels increase immensely due to genetic mutations, causing excessive p53 downregulation, thereby enhancing malignancy to extremities. Inhibition of MDM-2 to p53 interaction by potent inhibitors can be a potent therapy but the use of synthetic inhibitors poses many side effects. Natural dietary flavonoids like epicatechin possess high antioxidant and anti-carcinogenic properties. Molecular docking and MD simulation approaches were used to reveal the effectiveness of epicatechin in this regard, a high negative binding energy of -9.619 kcal/mol with Ki value of 82.34 nM and 6 hydrogen bonds with the leading residues responsible for MDM2 p53 interaction were noticed. MD simulation of 100 ns revealed that epicatechin continues to interact with the vital residues of MDM2 and p53 and occupies the hydrophobic p53-binding cleft in MDM2. Significant structural modifications in MDM2-p53 complex due to epicatechin interactions were observed. The increase in RMSD and Rg values of MDM2-p53 complex in presence of epicatechin provides evidence for the destabilization of complex. The extreme increase in RMSF values of p53 in turn indicates towards its reduced interaction with MDM2. Hence, epicatechin can promisingly treat adverse glioblastoma pathologies by inhibiting MDM2-p53 interactions, therefore exhaustive research is urgently demanded.