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Optimized Virtual Screening Workflow for the Identification of Novel G-Quadruplex Ligands
Teresa Kaserer1, Riccardo Rigo2, Philipp Schuster1
1Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria.
Researchers identified novel compounds that stabilize G-quadruplex DNA structures, offering new potential for cancer treatment by inhibiting cell proliferation. This study presents an optimized computational method for discovering these promising G-quadruplex ligands.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Computational Biology
Background:
- G-quadruplexes are alternative DNA secondary structures found in telomeres.
- These structures are crucial targets for cancer therapy as they inhibit telomere elongation and cell proliferation.
Purpose of the Study:
- To identify novel G-quadruplex ligands using computational methods.
- To validate and optimize an in silico workflow for G-quadruplex stabilizer discovery.
Main Methods:
- Generation and application of theoretically validated pharmacophore, shape-based models, and a docking protocol for virtual screening.
- Selection of top-ranked hits for biological testing using fluorescence melting assays.
- In vitro analysis of selected compounds and their analogues.
Main Results:
- Seven out of 32 tested virtual hits selectively stabilized G-quadruplexes over duplex DNA.
- Seven additional novel G-quadruplex ligands were identified through analogue analysis.
- Some identified compounds demonstrated higher potency than the reference compound berberine.
Conclusions:
- An optimized in silico workflow for identifying G-quadruplex stabilizers was proposed.
- Structurally novel and potent G-quadruplex stabilizing lead candidates were discovered.
- These findings offer promising avenues for developing new anti-cancer therapeutics.
