Insight Derived from Molecular Dynamics Simulation into the Selectivity Mechanism Targeting c-MYC G-Quadruplex

Stabilizing G-quadruplex (G4) structures formed in the c-MYC oncogene promoter represents a fundamental strategy for cancer therapy. However, most G4 stabilizers lack selectivity over various G4s in the genomes. By investigating the binding characteristics of a conjugated imidazole/carbazole (IZCZ-3) molecule with the G4s of c-MYC, c-KIT, and telomere through molecular docking and molecular dynamics simulations, the present study demonstrates that though the binding affinities between IZCZ-3 and the monomeric G4s are inconsistent with the experimental data, the dimeric c-MYC and c-KIT G4s can be targeted by IZCZ-3 through forming concomitant pi-pi stacking interactions with the intermolecular assembly producing significant contributions to the binding affinity. In the intermolecular dimeric G4-IZCZ-3 binding complexes, IZCZ-3 prefers the c-MYC G4 that has two exposed G-tetrads per monomer over the single G-tetrad-exposed c-KIT G4 by creating more aggregation effects. Taking the aggregation effects into account, the binding affinity order of IZCZ-3 follows c-MYC G4 > c-KIT G4 > telomeric G4, agreeing well with the experimental observation. Thus, the selectivity of IZCZ-3 for c-MYC G4 probably comes from its role in stabilizing the sandwichlike intermolecular aggregates, providing a framework for the development of selective stabilizers targeting c-MYC G4.