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

• Published in: ChemMedChem Vol. 19; no. 14; pp. e202400080 - n/a
• Main Authors: Zięba, Agata, Bartuzi, Damian, Stępnicki, Piotr, Matosiuk, Dariusz, Wróbel, Tomasz M., Laitinen, Tuomo, Castro, Marián, Kaczor, Agnieszka A.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 15.07.2024
• Subjects: Antidepressants; Antipsychotics; Binding; drug discovery; Ligands; Mental depression; Mental disorders; Molecular structure; Pharmacokinetics; Receptors; Schizophrenia; Screening; Serotonin; serotonin receptor; virtual screening; antipsychotics; serotonin receptor; Virtual Screening; antidepressants; Drug discovery
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202400080

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. Novel serotonin 5‐HT2A receptor ligands were identified in a structure‐based virtual screening campaign. These compounds displayed an interesting selectivity profile, including 5‐HT1A, 5‐HT7, and D2 receptors, characteristic for the second generation of antipsychotics. The reported compounds represent a promising starting point for further optimization campaigns. (Figure generated with BioRender.com)