title: Chemoproteomic Approach to Explore the Target Profile of GPCR ligands: Application to 5-HT1A and 5-HT6 Receptors.
abstract: Determination of the targets of a compound remains an essential aspect in drug discovery. A complete understanding of all binding interactions is critical to recognize in advance both therapeutic effects and undesired consequences. However, the complete polypharmacology of many drugs currently in clinical development is still unknown, especially in the case of G protein-coupled receptor (GPCR) ligands. In this work we have developed a chemoproteomic platform based on the use of chemical probes to explore the target profile of a compound in biological systems. As proof of concept, this methodology has been applied to selected ligands of the therapeutically relevant serotonin 5-HT1A and 5-HT6 receptors, and we have identified and validated some of their off-targets. This approach could be extended to other drugs of interest to study the targeted proteome in disease-relevant systems.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gamo
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: González-Vera
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Ainoa
authors.initials: A
authors.lastname: Rueda-Zubiaurre
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Dulce
authors.initials: D
authors.lastname: Alonso
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Henar
authors.initials: H
authors.lastname: Vázquez-Villa
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Martín-Couce
authors.affiliation: Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Palomares
authors.affiliation: Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares, CNIC, 28029, Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: López
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain. mluzlr@ucm.es.
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain. siortega@quim.ucm.es.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
mesh_terms: D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; D044282:Receptor, Serotonin, 5-HT1A
keywords: GPCRS; chemical probes; drug discovery; selectivity profiling; serotonin receptors