Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological Characterization
| Autor: | Adriaan P. IJzerman, Maarten L. J. Doornbos, Laura H. Heitman, Hilde Lavreysen, Gary Tresadern, Luc Peeters, José María Cid, Sophie C. Vermond, Laura Pérez-Benito, Andrés A. Trabanco, Xuesong Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Allosteric modulator
Pyridines Allosteric regulation Class C GPCR Covalent Interaction Ligands Receptors Metabotropic Glutamate 01 natural sciences Article 03 medical and health sciences Allosteric Regulation Drug Discovery Humans 030304 developmental biology G protein-coupled receptor 0303 health sciences Chemistry Small molecule Receptor–ligand kinetics Protein Structure Tertiary 0104 chemical sciences Molecular Docking Simulation Kinetics 010404 medicinal & biomolecular chemistry Mutagenesis Drug Design Biophysics Molecular Medicine Metabotropic glutamate receptor 2 Allosteric Site |
| Zdroj: | Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Journal of Medicinal Chemistry, 62(1), 223-233 Journal of Medicinal Chemistry |
| DOI: | 10.1021/acs.jmedchem.8b00051 |
| Popis: | Covalent labeling of G protein-coupled receptors (GPCRs) by small molecules is a powerful approach to understand binding modes, mechanism of action, pharmacology, and even facilitate structure elucidation. We report the first covalent positive allosteric modulator (PAM) for a class C GPCR, the mGlu2 receptor. Three putatively covalent mGlu2 PAMs were designed and synthesized. Pharmacological characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T7917.29×30 as the likely position of covalent interaction. We show how this covalent ligand can be used to characterize the PAM binding mode and that it is a valuable tool compound in studying receptor function and binding kinetics. Our findings advance the understanding of the mGlu2 PAM interaction and suggest that 2 is a valuable probe for further structural and chemical biology approaches. |
| Databáze: | OpenAIRE |
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