Binding of Flavonoid Derivatives to G-Quadruplex DNA Studied by Molecular Docking

Four guanines self-assemble into a planar G-quartet structure via Hoogsteen H-bonding. Several G-quartets can stack on top of each other to form a unique DNA secondary structure – G-quadruplex. Over 300,000 G-quadruplex forming sequences are present in the human genome including the telomere region. The telomeres are single-stranded tails at the end of chromosomes that provide protection against nucleases and genomic degradation. The telomere region shortens with every cell division, eventually reaching a critical point resulting in cell death. The telomere length is maintained in 80-90% of cancer cells by a reverse transcriptase (telomerase) that adds telomeric DNA fragments to the chromosome ends. Such continuous telomere extension results in “immortal” cell growth and replication, a characteristic of cancer. Because of this, telomerase in recent years has become a promising anti-cancer target. It is well known that the formation of G-quadruplexes in telomeres inhibits the activity of telomerase. Small molecules that can facilitate G-quadruplex formation have been developed as potential anti-cancer drugs. In the present work, we studied the binding of novel flavonoid derivatives to various G-quadruple DNA using computational tools. G-quadruplexes with different conformations including parallel, anti-parallel, and hybrid-type were used. Programs such as Spartan and ChemDraw3D were used for the creation of digital ligands, and AutoDockTools and Autodock Vina were used for finding probable and stable ligand-DNA conformations to determine the binding efficiency and stability. The preliminary calculations indicate that planar ligands, especially ring-based ligands, prefer to stack with the end G-quartets, while the sidechains fold into the large grooves between the DNA backbones. Planar ligands bind more effectively with parallel G-quadruplexes than anti-parallel and hybrid-type G-quadruplexes. Biophysical studies of the effective ligands identified from docking results with G-quadruplex DNA will be conducted in the future