Exploiting σ-hole interaction to design small uncharged ligand molecules to stabilize G-quadruplex-DNA: a computational study.

Small neutral seleno molecules were designed to stabilize G-quadruplex-DNA to accelerate the death of cancer cells. A new approach was considered in this study to design new ligands to stabilize G-quadruplex-DNA using the non-covalent σ-hole interaction. The systematic study has been performed with ligands in the absence and presence of σ-hole interaction to stabilize G-tetrad. Fluorine-substituted seleno ligands interact with the bases of G-quadruplex strongly with the σ-holes present in the ligands. The binding of the fluorinated ligands FSeCFSeCF SeF2(4) (75.0 kcal/mol) is stronger than that of BRACO-19 (70.0 kcal/mol) calculated at the same level of theory with G-tetrad. It is reported that BRACO-19 is employed to inhibit the enzymatic activity of telomerase. The calculated results also reveal the importance of optimum chain length of ligands to achieve a better binding ability with G-tetrad. The MESP calculations and AIM analysis corroborate the trends of binding of these ligand molecules with G-quadruplexes. The small neutral molecules possess considerable advantage to pass through the lipid bilayer of the cell membrane by passive transport and are of choice in biological research and for clinical trials. Graphical AbtractSmall neutral ligands with σ-holes can stabilize G-quadruplex to inhibit enzymatic activity of telomerase.