Discovery and inâ
vitro Evaluation of Novel Serotonin 5-HT2A Receptor Ligands Identified Through Virtual Screening.
ChemMedChem
; 19(14): e202400080, 2024 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-38619283
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 inâ
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 inâ
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptor 5-HT2A de Serotonina
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article