Structure-based development of a subtype-selective orexin 1 receptor antagonist
| Autor: | Dorothee Weikert, Peter Kolb, Peter Gmeiner, Harald Hübner, Christopher J. Langmead, Frank Kraus, Jakub Gunera, Daniel M. Rosenbaum, Jie Yin, Theresa Pröll, Jan Hellmann, Matthäus Drabek |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.drug_class
Protein Conformation Molecular Dynamics Simulation Ligands Receptors G-Protein-Coupled Structure-Activity Relationship Orexin Receptors medicine Binding site Receptor G protein-coupled receptor Multidisciplinary Binding Sites Crystallography Chemistry Suvorexant Antagonist Biological Sciences Receptor antagonist Orexin receptor Orexin Molecular Docking Simulation Kinetics Drug Design Biophysics Orexin Receptor Antagonists Protein Binding |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | Orexins are neuropeptides that activate the rhodopsin-like G protein-coupled receptors OX1R and OX2R. The orexin system plays an important role in the regulation of the sleep-wake cycle and the regulation of feeding and emotions. The nonselective orexin receptor antagonist suvorexant has been the first drug on the market targeting the orexin system and is prescribed for the treatment of insomnia. Subtype-selective OX1R antagonists are valuable tools to further investigate the functions and physiological role of the OX1R in vivo and promising lead compounds for the treatment of drug addiction, anxiety, pain or obesity. Starting from the OX1R and OX2R crystal structures bound to suvorexant, we exploited a single amino acid difference in the orthosteric binding site by using molecular docking and structure-based drug design to optimize ligand interactions with the OX1R while introducing repulsive interactions with the OX2R. A newly established enantiospecific synthesis provided ligands showing up to 75-fold selectivity for the OX1R over the OX2R subtype. The structure of a new OX1R antagonist with subnanomolar affinity (JH112) was determined by crystallography in complex with the OX1R and corresponded closely to the docking-predicted geometry. JH112 exhibits high selectivity over a panel of different GPCRs, is able to cross the blood–brain barrier and acts as slowly diffusing and insurmountable antagonist for G(q) protein activation and in particular β-arrestin-2 recruitment at OX1R. This study demonstrates the potential of structure-based drug design to develop more subtype-selective GPCR ligands with potentially reduced side effects and provides an attractive probe molecule and lead compound. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|