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

Stabilizing G-quadruplex (G4) structures formed in the 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 , 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 and G4s can be targeted by IZCZ-3 through forming concomitant π-π 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 G4 that has two exposed G-tetrads per monomer over the single G-tetrad-exposed G4 by creating more aggregation effects. Taking the aggregation effects into account, the binding affinity order of IZCZ-3 follows G4 > G4 > telomeric G4, agreeing well with the experimental observation. Thus, the selectivity of IZCZ-3 for G4 probably comes from its role in stabilizing the sandwichlike intermolecular aggregates, providing a framework for the development of selective stabilizers targeting G4.