title: Detection of new biased agonists for the serotonin 5-HT2A receptor: modeling and experimental validation.
abstract: Detection of biased agonists for the serotonin 5-HT2A receptor can guide the discovery of safer and more efficient antipsychotic drugs. However, the rational design of such drugs has been hampered by the difficulty detecting the impact of small structural changes on signaling bias. To overcome these difficulties, we characterized the dynamics of ligand-receptor interactions of known biased and balanced agonists using molecular dynamics simulations. Our analysis revealed that interactions with residues S5.46 and N6.55 discriminate compounds with different functional selectivity. Based on our computational predictions, we selected three derivatives of the natural balanced ligand serotonin and experimentally validated their ability to act as biased agonists. Remarkably, our approach yielded compounds promoting an unprecedented level of signaling bias at the 5-HT2A receptor, which could help interrogate the importance of particular pathways in conditions like schizophrenia.
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.).
authors: Maria
authors: M
authors: Martí-Solano
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.).
authors: Alba
authors: A
authors: Iglesias
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.).
authors: Gianni
authors: G
authors: de Fabritiis
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.).
authors: Ferran
authors: F
authors: Sanz
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.).
authors: José
authors: J
authors: Brea
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.).
authors: M Isabel
authors: MI
authors: Loza
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.) jana.selent@upf.edu manuel.pastor@upf.edu.
authors: Manuel
authors: M
authors: Pastor
authors: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.) jana.selent@upf.edu manuel.pastor@upf.edu.
authors: Jana
authors: J
authors: Selent
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D012701:Serotonin