title: Tandem application of ligand-based virtual screening and G4-OAS assay to identify novel G-quadruplex-targeting chemotypes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Naples 80126, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Musumeci
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Jussara
authors.initials: J
authors.lastname: Amato
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Zizza
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Naples 80126, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Platella
authors.affiliation: DiSTABiF, Second University of Naples, Caserta 81100, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cingolani
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Rome 00144, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Randazzo
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Giancola
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy. Electronic address: bruno.pagano@unina.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pagano
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Naples 80126, Italy. Electronic address: daniela.montesarchio@unina.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Montesarchio
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects*; D006151:Guanosine / Q000737:chemistry / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D016615:Telomere / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008024:Ligands; D054852:Small Molecule Libraries; D006151:Guanosine
keywords: Anticancer agents; Drug discovery; G-quadruplex; Virtual screening