Chemoproteomic Approach to Explore the Target Profile of GPCR ligands: Application to 5‐HT1A and 5‐HT6 Receptors |
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| Authors: | Dr Ainoa Rueda‐Zubiaurre Dr Dulce Alonso Dr Henar Vázquez‐Villa Dr Lidia Martín‐Couce Dr Óscar Palomares Dr Juan A López Prof?Dr Mar Martín‐Fontecha Prof?Dr Bellinda Benhamú Prof?Dr María L López‐Rodríguez Prof?Dr Silvia Ortega‐Gutiérrez |
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| Institution: | 1. Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain;2. Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain;3. Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain |
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| 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. |
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| Keywords: | chemical probes drug discovery GPCRS selectivity profiling serotonin receptors |
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