Computational Analysis of the Homologous Mouse Double RINGs Interface for Targeted Anticancer Drug Design

Background/Objectives: The new yearly 1.1 million cancer cases and considerably increasing mortality, after decades of decline, require urgent and effective therapy. Targeted anticancer therapy is an attractive strategy for treating cancer by targeting critical receptors. The MDM2-MDMX RING heterodimer downregulates the p53 tumor suppressor pathway, making its disruption a primary therapeutic strategy in oncology. This study evaluates a series of novel inhibitors against the MDM2-MDMX RING interface to identify potent candidates that overcome the binding affinity and structural stability limitations of current small-molecule options like HLI373.

Methods

Comprehensive computational simulations and MM/PBSA energy calculations were performed on five inhibitor complexes: Hinokiflavone, MMRi62, MMRi64, MMRi71, and HLI373. Structural stability, flexibility, and compactness were rigorously analyzed across a 200 ns molecular dynamics simulation trajectory using Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) metrics alongside Principal Component Analysis.