Selectivity of small molecule ligands for parallel and anti-parallel DNA G-quadruplex structures

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• DNA quadruplexes, such as those from the human telomeric repeat sequence (h-Tel) and the c-kit promoter, form diverse structures (parallel and anti-parallel).
• Ligand interactions with these structures are crucial for understanding their biological roles and for developing targeted therapies.

Purpose of the Study:

• To investigate the binding interactions of small molecules with different DNA quadruplex structures.
• To determine how ligand architecture influences selectivity for parallel versus anti-parallel quadruplex conformations.
• To assess the structural plasticity of h-Tel and c-kit quadruplexes in response to ligand binding.

Main Methods:

• Circular Dichroism (CD) spectroscopy.
• Electrospray Ionization Mass Spectrometry (ESI-MS).
• Molecular modeling studies.

Main Results:

• The heteroaromatic 1,4-triazole (TRZ) showed some selectivity for parallel h-Tel quadruplexes, while the RHPS4 cation preferred anti-parallel conformations.
• The c-kit parallel quadruplex exhibited limited structural plasticity compared to h-Tel.
• Quantitative ESI-MS revealed ligand binding at both ends of the quadruplexes, with differing affinities for h-Tel and c-kit.

Conclusions:

• Small molecule design can exploit differences in quadruplex structure and plasticity for selective targeting.
• Understanding ligand-induced structural changes is key for developing novel quadruplex-targeting drugs.
• Findings may guide the design of agents targeting telomerase and oncogenic pathways.