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Updated: Mar 9, 2026
Author Spotlight: Characterizing DNA G-Quadruplex by Bis-3-Chloropiperidine Based Chemical Mapping
Published on: May 12, 2023
Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization
Roberta Rocca1, Federica Moraca1, Giosuè Costa1
1Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", viale Europa, 88100, Catanzaro, Italy.
Background:
Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition.
Methods:
Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel2) and TERRA (TERRA2). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations.
Results:
Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2/TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed.
Conclusions:
Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s.
General Significance:
The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
Insights
Researchers identified novel compounds targeting G-quadruplex DNA and RNA structures. These G-quadruplex binders show potential for anticancer therapies by inhibiting telomerase.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Telomere DNA (Tel) and telomeric repeat-containing RNA (TERRA) are transcribed in mammalian cells.
- TERRA is involved in crucial biological processes and represents a potential anticancer target.
- Dual Tel/TERRA G-quadruplex (G4) binders offer an innovative strategy for telomerase inhibition.
Purpose of the Study:
- To discover and characterize novel dual and selective G-quadruplex (G4) binders for Tel and TERRA.
- To explore innovative ligand chemical scaffolds with anticancer potential.
Main Methods:
- Molecular docking simulations of known ligands on Tel2 and TERRA2 G4 structures.
- Generation of structure-based pharmacophore models for virtual screening of natural compounds.
- Biophysical assays (circular dichroism, mass spectrometry) to characterize ligand-G4 interactions.
Main Results:
- Identification of three G4 binders through biophysical assays.
- Compound 7 demonstrated dual Tel2/TERRA2 G4-ligand activity.
- Compounds 15 and 17 exhibited preferential thermal stabilization for Tel2 DNA.
Conclusions:
- The study successfully identified novel chemical scaffolds for Tel and TERRA G4 ligands.
- Results pave the way for lead optimization to enhance selectivity and stabilizing effects.
- This integrated approach of molecular modeling and biophysical assays provides a promising strategy for anticancer drug discovery.
