Exploiting hydrogen bonding interactions to probe smaller linear and cyclic diamines binding to G-quadruplexes: a DFT...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• G-quadruplexes are DNA structures in telomeres and oncogene promoters, targeted for anti-cancer drug development.
• Protonated diamines are explored for binding to G-quadruplex DNA via hydrogen bonding and π-stacking interactions.

Purpose of the Study:

• To investigate the binding affinity of linear and cyclic protonated diamines to G-quadruplex DNA.
• To compare the binding strength of these ligands with known G-quadruplex binders like BRACO-19.

Main Methods:

• Density Functional Theory (DFT) calculations (M06-2X/6-31G(d)//B3LYP/6-31+G(d)) to determine binding energies.
• Atoms-in-Molecules (AIM) analysis to understand interaction types.
• Molecular dynamics (MD) simulations using GROMACS to assess binding modes.

Main Results:

• Cyclic ee-1,2-CHDA demonstrated strong binding affinity (∼70.0 kcal mol⁻¹) to G-tetrads, significantly exceeding that of linear diamines.
• Ligands showed higher binding preference for G-quadruplexes than DNA duplexes.
• A designed molecule (9) mimicking BRACO-19 also showed efficient binding via H-bonding.
• Binding affinity of ee-1,2-CHDA surpassed that of the acridine-based ligand BRACO-19.

Conclusions:

• Cyclic protonated diamines, especially ee-1,2-CHDA, are potent binders to G-quadruplex DNA through hydrogen bonding.
• These findings highlight a novel binding motif distinct from π-delocalized systems, offering new avenues for G-quadruplex stabilizing drug design.