A Fragment-Based Approach for the Development of G-Quadruplex Ligands: Role of the Amidoxime Moiety

Martina Tassinari, Alberto Lena, Elena Butovskaya, Valentina Pirota, Matteo Nadai, Mauro Freccero, Filippo Doria, Sara N Richter

Research output: Contribution to journalArticlepeer-review


G-quadruplex (G4) nucleic acid structures have been reported to be involved in several human pathologies, including cancer, neurodegenerative disorders and infectious diseases; however, G4 targeting compounds still need implementation in terms of drug-like properties and selectivity in order to reach the clinical use. So far, G4 ligands have been mainly identified through high-throughput screening methods or design of molecules with pre-set features. Here, we describe the development of new heterocyclic ligands through a fragment-based drug discovery (FBDD) approach. The ligands were designed against the major G4 present in the long terminal repeat (LTR) promoter region of the human immunodeficiency virus-1 (HIV-1), the stabilization of which has been shown to suppress viral gene expression and replication. Our method is based on the generation of molecular fragment small libraries, screened against the target to further elaborate them into lead compounds. We screened 150 small molecules, composed by structurally and chemically different fragments, selected from commercially available and in-house compounds; synthetic elaboration yielded several G4 ligands and two final G4 binders, both embedding an amidoxime moiety; one of these two compounds showed preferential binding for the HIV-1 LTR G4. This work presents the discovery of a novel potential pharmacophore and highlights the possibility to apply a fragment-based approach to develop G4 ligands with unexpected chemical features.

Original languageEnglish
Issue number8
Publication statusPublished - Jul 27 2018
Externally publishedYes


  • Drug Design
  • Drug Evaluation, Preclinical
  • G-Quadruplexes
  • HIV Long Terminal Repeat/drug effects
  • Heterocyclic Compounds/chemical synthesis
  • Ligands
  • Molecular Structure
  • Oximes/chemistry
  • Small Molecule Libraries/chemistry


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