Density Functional Theory Investigation of the Binding Affinity of Nitrogen Heterocycles and Drug-Like Molecules to...

G-Quadruplexes (G4) are nucleic acid secondary structures implicated in the regulation of oncogenes and represent promising therapeutic targets. Using density functional theory (DFT), we systematically investigated the binding affinity of nitrogen-containing heterocycles and drug-like molecules to guanine tetrads in the G4 model structure. Our results show that heterocycles with multiple, clustered nitrogen atoms bind most strongly, while larger fused unsaturated systems, such as quinoline, are also favored. Saturated scaffolds generally exhibit weak binding, except for azepane and 1,3-diazepane, which display an appreciable affinity. Structural analysis indicates that maintaining a parallel orientation with the tetrad contributes to complex stability, whereas the distance between the ligand fragments has little effect. These findings highlight key structural determinants for G4-ligand interactions and provide a framework for the rational design of G4-targeting molecules with potential therapeutic applications.