Identification of a selective G-quadruplex DNA binder using a multistep virtual screening approach

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Bioinformatics

Background:

• G-quadruplex DNA structures are increasingly recognized as potential therapeutic targets.
• Selective targeting of G-quadruplex DNA over duplex DNA is crucial for drug development.
• Virtual screening offers an efficient approach for identifying potential drug candidates.

Purpose of the Study:

• To develop and apply a structure-based virtual screening strategy for identifying small molecules selective for G-quadruplex DNA.
• To differentiate ligands that bind G-quadruplexes from those that bind duplex DNA.

Main Methods:

• Multistep structure-based virtual screening incorporating both G-quadruplex and duplex DNA models.
• Surface Plasmon Resonance (SPR) for binding kinetics analysis.
• Förster Resonance Energy Transfer (FRET)-based competition assays.
• Luciferase activity assays to assess biological activity.

Main Results:

• A virtual screening workflow was established to prioritize compounds based on predicted binding to G-quadruplex DNA.
• Thirteen compounds were selected for experimental validation.
• One identified ligand exhibited significant selectivity for binding to G-quadruplex structures over duplex DNA.

Conclusions:

• The developed virtual screening approach is effective in identifying G-quadruplex selective ligands.
• The outstanding ligand identified represents a promising candidate for further investigation in G-quadruplex-related therapeutic strategies.