Study of the interaction between indole-based compounds and biologically relevant G-quadruplexes

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysics

Background:

• G-quadruplexes (G4s) are crucial secondary DNA structures regulating vital cellular processes.
• G4s are increasingly recognized as promising therapeutic targets for drug development.
• Small molecules that bind and stabilize G4s are key to their therapeutic potential.

Purpose of the Study:

• To synthesize novel indole-based compounds.
• To investigate the interaction of these compounds with biologically relevant G-quadruplexes (c-MYC and 22AG).
• To evaluate the potential of these compounds as drug leads for G4-targeting therapies.

Main Methods:

• Chemical synthesis of indole-based ligands.
• Biophysical techniques to study ligand-G4 interactions.
• Nuclear Magnetic Resonance (NMR) spectroscopy (1H and NOESY) for structural analysis.
• Molecular docking simulations for computational validation.

Main Results:

• Synthesized indole derivatives demonstrated specificity for G-quadruplex structures.
• Ligands could discriminate between different G4 topologies (parallel and hybrid-1).
• Compound 3 exhibited a 2:1 binding ratio with the c-MYC G-quadruplex, interacting at external tetrads and loops/grooves.
• NMR and docking studies corroborated the binding mode of compound 3 to the c-MYC G-quadruplex.

Conclusions:

• Indole-based compounds are effective G4 binders and stabilizers.
• These ligands display selectivity for specific G-quadruplex structures.
• Compound 3 represents a promising lead for further optimization in G4-targeted drug discovery.