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Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
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Exploiting σ-hole interaction to design small uncharged ligand molecules to stabilize G-quadruplex-DNA: a
Mrinal Kanti Si1,2, Anusuya Saha1, Bishwajit Ganguly3,4
1Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR-Central Salt & Marine Chemicals Research Institute, Bhavnagar, Gujarat, 364002, India.
Journal of Molecular Modeling
|February 3, 2020
Summary
New fluorine-substituted seleno molecules stabilize G-quadruplex-DNA by utilizing σ-hole interactions, offering a promising strategy to accelerate cancer cell death and inhibit telomerase activity.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Molecular Biology
Background:
- G-quadruplex DNA structures are crucial targets for cancer therapy.
- Stabilizing G-quadruplex DNA can lead to cancer cell death.
- Existing ligands like BRACO-19 are used to inhibit telomerase.
Purpose of the Study:
- To design novel neutral seleno molecules for G-quadruplex DNA stabilization.
- To investigate the role of non-covalent σ-hole interactions in ligand design.
- To explore new therapeutic strategies against cancer by targeting G-quadruplex DNA.
Main Methods:
- Computational design and systematic study of seleno ligands.
- Analysis of ligand interactions with G-quadruplex using σ-hole interactions.
- Quantum chemical calculations (MESP and AIM analysis) to determine binding affinities.
Main Results:
- Fluorine-substituted seleno ligands demonstrated strong binding with G-quadruplex tetrads via σ-hole interactions.
- The ligand FSeCF2SeCF2SeF2(4) exhibited superior binding (~75.0 kcal/mol) compared to BRACO-19 (~70.0 kcal/mol).
- Optimal ligand chain length was found to be critical for enhanced binding affinity.
Conclusions:
- Small neutral seleno molecules with σ-hole interactions represent a potent new class of G-quadruplex stabilizers.
- These ligands show potential for inhibiting telomerase and promoting cancer cell death.
- The ability of these molecules to cross cell membranes via passive transport makes them suitable for clinical applications.
