Structure-Based Discovery of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-Induced Osteoclastogenesis Inhibitors

Vagelis Rinotas, Fotini Liepouri, Maria Dimitra Ouzouni, Niki Chalkidi, Christos Papaneophytou, Mariza Lampropoulou, Veroniki P. Vidali, George Kontopidis, Elias Couladouros, Elias Eliopoulos, Athanasios Papakyriakou, Eleni Douni

Research output: Contribution to journalArticlepeer-review


Receptor activator of nuclear factor-κB ligand (RANKL) has been actively pursued as a therapeutic target for osteoporosis, given that RANKL is the master mediator of bone resorption as it promotes osteoclast differentiation, activity and survival. We employed a structure-based virtual screening approach comprising two stages of experimental evaluation and identified 11 commercially available compounds that displayed dose-dependent inhibition of osteoclastogenesis. Their inhibitory effects were quantified through TRAP activity at the low micromolar range (IC50 < 5 μΜ), but more importantly, 3 compounds displayed very low toxicity (LC50 > 100 μΜ). We also assessed the potential of an N-(1-aryl-1H-indol-5-yl)aryl-sulfonamide scaffold that was based on the structure of a hit compound, through synthesis of 30 derivatives. Their evaluation revealed 4 additional hits that inhibited osteoclastogenesis at low micromolar concentrations; however, cellular toxicity concerns preclude their further development. Taken together with the structure–activity relationships provided by the hit compounds, our study revealed potent inhibitors of RANKL-induced osteoclastogenesis of high therapeutic index, which bear diverse scaffolds that can be employed in hit-to-lead optimization for the development of therapeutics against osteolytic diseases.

Original languageEnglish
Article number11290
JournalInternational Journal of Molecular Sciences
Issue number14
Publication statusPublished - Jul 2023


  • cell-based assay
  • compound solubility
  • computer-aided drug discovery
  • small-molecule inhibitor
  • synthesis
  • toxicity evaluation
  • virtual screening


Dive into the research topics of 'Structure-Based Discovery of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-Induced Osteoclastogenesis Inhibitors'. Together they form a unique fingerprint.

Cite this