Molecular Insights into the Specific Targeting of G-Quadruplex by Thiazole Peptides

Stabilization of a G-quadruplex (G4) in the promotor of the proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, , preferentially stabilizes the G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of and its analogue to the G4s from the promotors of , , , and . Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both and can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for G4 relative to other promotor G4s, with exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of towards G4 provide valuable information to guide the development of new selective G4 stabilizers.