Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor Ligand
Many 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....
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MDPI AG
2025-05-01
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| author | Agata Zięba Ewa Kędzierska Michał K. Jastrzębski Tadeusz Karcz Agnieszka Olejarz-Maciej Agata Sumara Tuomo Laitinen Tomasz M. Wróbel Emilia Fornal Marián Castro Agnieszka A. Kaczor |
| author_facet | Agata Zięba Ewa Kędzierska Michał K. Jastrzębski Tadeusz Karcz Agnieszka Olejarz-Maciej Agata Sumara Tuomo Laitinen Tomasz M. Wróbel Emilia Fornal Marián Castro Agnieszka A. Kaczor |
| author_sort | Agata Zięba |
| collection | DOAJ |
| description | Many 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-HT<sub>1A</sub>, 5-HT<sub>2A</sub>, and D<sub>2</sub> receptors. Through these investigations, we discovered that SERAAK1 binds to the orthosteric pocket of the 5-HT<sub>2A</sub> 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-HT<sub>2A</sub> 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. |
| format | Article |
| id | doaj-art-9be7feb2cdb2485aa12e82bb01113f86 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-9be7feb2cdb2485aa12e82bb01113f862025-08-20T03:14:42ZengMDPI AGMolecules1420-30492025-05-013010216510.3390/molecules30102165Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor LigandAgata Zięba0Ewa Kędzierska1Michał K. Jastrzębski2Tadeusz Karcz3Agnieszka Olejarz-Maciej4Agata Sumara5Tuomo Laitinen6Tomasz M. Wróbel7Emilia Fornal8Marián Castro9Agnieszka A. Kaczor10Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., 20093 Lublin, PolandDepartment of Pharmacology and Pharmacodynamics, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., 20093 Lublin, PolandDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., 20093 Lublin, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, 30688 Kraków, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, 30688 Kraków, PolandDepartment of Bioanalytics, Medical University of Lublin, Jaczewskiego 8b St., 20-090 Lublin, PolandSchool of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70211 Kuopio, FinlandDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., 20093 Lublin, PolandDepartment of Bioanalytics, Medical University of Lublin, Jaczewskiego 8b St., 20-090 Lublin, PolandDepartment of Pharmacology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Avda de Barcelona, 15782 Santiago de Compostela, SpainDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., 20093 Lublin, PolandMany 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-HT<sub>1A</sub>, 5-HT<sub>2A</sub>, and D<sub>2</sub> receptors. Through these investigations, we discovered that SERAAK1 binds to the orthosteric pocket of the 5-HT<sub>2A</sub> 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-HT<sub>2A</sub> 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.https://www.mdpi.com/1420-3049/30/10/21655-HT<sub>2A</sub> receptorADMETantidepressantsantipsychoticsin vivo studiesmolecular modeling |
| spellingShingle | Agata Zięba Ewa Kędzierska Michał K. Jastrzębski Tadeusz Karcz Agnieszka Olejarz-Maciej Agata Sumara Tuomo Laitinen Tomasz M. Wróbel Emilia Fornal Marián Castro Agnieszka A. Kaczor Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor Ligand Molecules 5-HT<sub>2A</sub> receptor ADMET antidepressants antipsychotics in vivo studies molecular modeling |
| title | Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor Ligand |
| title_full | Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor Ligand |
| title_fullStr | Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor Ligand |
| title_full_unstemmed | Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor Ligand |
| title_short | Synthesis, Experimental and Computational Evaluation of SERAAK1 as a 5-HT<sub>2A</sub> Receptor Ligand |
| title_sort | synthesis experimental and computational evaluation of seraak1 as a 5 ht sub 2a sub receptor ligand |
| topic | 5-HT<sub>2A</sub> receptor ADMET antidepressants antipsychotics in vivo studies molecular modeling |
| url | https://www.mdpi.com/1420-3049/30/10/2165 |
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