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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.
Biochimica Et Biophysica Acta. General Subjects
|December 28, 2016
Summary
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.
