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Tandem application of ligand-based virtual screening and G4-OAS assay to identify novel G-quadruplex-targeting
Domenica Musumeci1, Jussara Amato2, Pasquale Zizza3
1Department of Chemical Sciences, University of Naples Federico II, Naples 80126, Italy.
Background:
G-quadruplex (G4) structures are key elements in the regulation of cancer cell proliferation and their targeting is deemed to be a promising strategy in anticancer therapy.
Methods:
A tandem application of ligand-based virtual screening (VS) calculations together with the experimental G-quadruplex on Oligo Affinity Support (G4-OAS) assay was employed to discover novel G4-targeting compounds. The interaction of the selected compounds with the investigated G4 in solution was analysed through a series of biophysical techniques and their biological activity investigated by immunofluorescence and MTT assays.
Results:
A focused library of 60 small molecules, designed as putative G4 groove binders, was identified through the VS. The G4-OAS experimental screening led to the selection of 7 ligands effectively interacting with the G4-forming human telomeric DNA. Evaluation of the biological activity of the selected compounds showed that 3 ligands of this sub-library induced a marked telomere-localized DNA damage response in human tumour cells.
Conclusions:
The combined application of virtual and experimental screening tools proved to be a successful strategy to identify new bioactive chemotypes able to target the telomeric G4 DNA. These compounds may represent useful leads for the development of more potent and selective G4 ligands.
General Significance:
Expanding the repertoire of the available G4-targeting chemotypes with improved physico-chemical features, in particular aiming at the discovery of novel, selective G4 telomeric ligands, can help in developing effective anti-cancer drugs with fewer side effects. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
Insights
Researchers identified novel anticancer compounds targeting G-quadruplex (G4) DNA structures. This combined virtual and experimental screening approach yielded promising leads for developing selective G4 telomeric ligands for cancer therapy.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- G-quadruplex (G4) structures are crucial in regulating cancer cell proliferation.
- Targeting G4 structures presents a promising strategy for anticancer therapy.
Purpose of the Study:
- To discover novel G4-targeting compounds using a combined virtual and experimental screening approach.
- To identify ligands that interact with G4 structures, particularly telomeric G4 DNA.
- To evaluate the biological activity and potential anticancer effects of identified G4 ligands.
Main Methods:
- Ligand-based virtual screening (VS) was employed to identify potential G4 binders.
- Experimental screening using the G-quadruplex on Oligo Affinity Support (G4-OAS) assay was performed.
- Biophysical techniques, immunofluorescence, and MTT assays were used to analyze compound interactions and biological activity.
Main Results:
- A focused library of 60 small molecules was identified via VS as putative G4 groove binders.
- Seven ligands were selected through G4-OAS assay for effectively interacting with human telomeric G4 DNA.
- Three of these ligands induced a significant telomere-localized DNA damage response in human tumor cells.
Conclusions:
- The integrated virtual and experimental screening strategy successfully identified novel bioactive chemotypes targeting telomeric G4 DNA.
- These identified compounds serve as valuable leads for developing more potent and selective G4 ligands.
- Further development of these compounds could lead to effective anti-cancer drugs with potentially reduced side effects.
