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Discovery and in vitro Evaluation of Novel Serotonin 5-HT 2A Receptor Ligands Identified Through Virtual Screening.

Agata ZiębaDamian BartuziPiotr StępnickiDariusz MatosiukTomasz M WróbelTuomo LaitinenMarián CastroAgnieszka A Kaczor
Published in: ChemMedChem (2024)
The 5-HT 2A receptor is a molecular target of high pharmacological importance. Ligands of this protein, particularly atypical antipsychotics, are useful in the treatment of numerous mental disorders, including schizophrenia and major depressive disorder. Structure-based virtual screening using a 5-HT 2A receptor complex was performed to identify novel ligands for the 5-HT 2A receptor, serving as potential antidepressants. From the Enamine screening library, containing over 4 million compounds, 48 molecules were selected for subsequent experimental validation. These compounds were tested against the 5-HT 2A receptor in radioligand binding assays. From the tested batch, six molecules were identified as ligands of the main molecular target and were forwarded to a more detailed in vitro profiling. This included radioligand binding assays at 5-HT 1A , 5-HT 7 , and D 2 receptors and functional studies at 5-HT 2A receptors. These compounds were confirmed to show a binding affinity for at least one of the targets tested in vitro. The success rate for the inactive template-based screening reached 17 %, while it was 9 % for the active template-based screening. Similarity and fragment analysis indicated the structural novelty of the identified compounds. Pharmacokinetics for these molecules was determined using in silico approaches.
Keyphrases
  • major depressive disorder
  • binding protein
  • bipolar disorder
  • high throughput
  • risk assessment
  • single cell
  • mass spectrometry
  • climate change
  • molecularly imprinted