FDA-approved drugs selected using virtual screening bind specifically to G-quadruplex DNA

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Genetics

Background:

• Guanine-rich sequences in telomeres and oncogene promoters can form G-quadruplex structures.
• G-quadruplex stabilization is a known mechanism for telomerase inhibitors.

Purpose of the Study:

• To identify FDA-approved compounds with the potential to bind G-quadruplex DNA using virtual screening.
• To develop theoretical models for predicting G-quadruplex DNA binders.
• To validate the binding and stabilizing effects of predicted compounds on G-quadruplex structures.

Main Methods:

• Virtual screening of FDA-approved compounds against G-quadruplex DNA.
• Development of theoretical models based on known G-quadruplex stabilizers.
• Experimental validation using fluorescence resonance energy transfer (FRET) and fluorescent intercalator displacement assays.
• Testing binding affinity to human telomeric and oncogene promoter sequences (c-myc, K-ras).

Main Results:

• Six compounds were predicted to bind G-quadruplex DNA.
• Prochloroperazine, promazine, and chlorpromazine demonstrated significant stabilization and binding to G-quadruplex structures.
• These compounds also bound to oncogene promoter sequences and showed selectivity for G-quadruplex over duplex DNA.
• Amitriptyline, imipramine, and loxapine showed weaker stabilization but still bound to G-quadruplex.

Conclusions:

• Prochloroperazine, promazine, and chlorpromazine are effective binders and stabilizers of G-quadruplex DNA.
• These compounds exhibit selectivity for G-quadruplex structures, suggesting potential therapeutic applications.
• The study validates the use of virtual screening and theoretical modeling for identifying G-quadruplex-targeting compounds.