Discovery and in vitro Evaluation of Novel Serotonin 5-HT2A Receptor Ligands Identified Through Virtual Screening

ChemMedChem. 2024 Jul 15;19(14):e202400080. doi: 10.1002/cmdc.202400080. Epub 2024 May 29.

Abstract

The 5-HT2A 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-HT2A receptor complex was performed to identify novel ligands for the 5-HT2A 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-HT2A 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-HT1A, 5-HT7, and D2 receptors and functional studies at 5-HT2A 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.

Keywords: antidepressants; antipsychotics; drug discovery; serotonin receptor; virtual screening.

MeSH terms

  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptor, Serotonin, 5-HT2A* / chemistry
  • Receptor, Serotonin, 5-HT2A* / metabolism
  • Structure-Activity Relationship

Substances

  • Receptor, Serotonin, 5-HT2A
  • Ligands