Zięba, AgataKędzierska, EwaJastrzębski, Michał K.Karcz, TadeuszOlejarz-Maciej, AgnieszkaSumara, AgataLaitinen, TuomoWróbel, Tomasz M.Fornal, EmiliaCastro Pérez, María de los ÁngelesKaczor, Agnieszka A.2025-05-192025-05-192025-05-14Zięba, A.; Kędzierska, E.; Jastrzębski, M.K.; Karcz, T.; Olejarz-Maciej, A.; Sumara, A.; Laitinen, T.; Wróbel, T.M.; Fornal, E.; Castro, M.; et al. Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT2A Receptor Ligand. Molecules 2025, 30, 2165. https://doi.org/10.3390/ molecules301021651420-3049https://hdl.handle.net/10347/41629Many drug discovery efforts have identified potentially promising molecules; however, a common limitation of these reports is the lack of further experimental confirmation of pharmacokinetic properties and behavioral effects of discovered compounds. In this study, we aim to address this limitation. Therefore, we build on our previous virtual screening campaign by synthesizing, analyzing in silico, and evaluating experimentally the SERAAK1 compound, which was initially identified as a ligand for 5-HT1A, 5-HT2A, and D2 receptors. Through these investigations, we discovered that SERAAK1 binds to the orthosteric pocket of the 5-HT2A receptor in a similar mechanism to that known for marketed antipsychotic medications. Molecular dynamics simulations revealed that the SERAAK1 compound remains stable in the orthosteric binding pocket of the 5-HT2A receptor. The determination of the ADMET parameters indicated the directions for further optimization of the compounds. In vivo studies demonstrated the anxiolytic and antidepressant properties of the SERAAK1 compound.engAttribution 4.0 International© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) licensehttp://creativecommons.org/licenses/by/4.0/5-HT2A receptorADMETAntidepressantsAntipsychoticsIn vivo studiesMolecular modeling320808 Mecanismos de acción de los medicamentos320808 Mecanismos de acción de los medicamentos320909 Psicofarmacología320990 Farmacología experimentaljournal article10.3390/molecules30102165open access