Novel G-quadruplex stabilizing agents: in-silico approach and dynamics.

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• G-rich repetitive DNA at telomeres forms G-quadruplex structures essential for genomic stability.
• Stabilizing G-quadruplexes is a key strategy for developing novel anticancer therapeutics.
• Identifying selective G-quadruplex ligands is crucial for drug design.

Purpose of the Study:

• To identify potential G-quadruplex stabilizing agents using in silico methods.
• To investigate the interaction of lead compounds with G-quadruplexes through molecular dynamics and experimental validation.
• To assess the selectivity of identified ligands for G-quadruplexes over duplex DNA.

Main Methods:

• In silico molecular docking screening of a small molecule library.
• Molecular Dynamics (MD) simulations to study ligand-G-quadruplex interactions.
• Fluorescence spectroscopy to validate binding and assess selectivity.
• Nuclear Magnetic Resonance (NMR) spectroscopy to confirm ligand binding.
• Computational analysis of molecular properties and ADMET predictions.

Main Results:

• Two molecules, A and B, exhibited favorable docking scores and were selected for further study.
• Fluorescence spectroscopy confirmed binding of ligands A and B to G-quadruplexes, indicated by spectral blue shifts.
• Ligands A and B showed high selectivity, binding to G-quadruplexes but not to duplex DNA.
• NMR experiments confirmed the binding of both molecules to a 23-mer G-quadruplex.
• Computational analysis revealed that electrostatic interactions govern ligand binding to G-quadruplexes.

Conclusions:

• Molecules A and B are potent and selective G-quadruplex binders.
• These ligands demonstrate potential as lead compounds for developing novel anticancer therapeutics.
• The study provides valuable insights into the design of G-quadruplex stabilizing agents.