Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor
| Autor: | Peter Kolb, Jakub Gunera, Daniel M. Rosenbaum, Jillian G. Baker, Niek van Hilten |
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| Rok vydání: | 2020 |
| Předmět: |
Agonist
Stereochemistry medicine.drug_class Plasma protein binding CHO Cells Ligands 01 natural sciences 03 medical and health sciences Structure-Activity Relationship Cricetulus Orexin Receptors Drug Discovery medicine Structure–activity relationship Animals Humans Receptor 030304 developmental biology 0303 health sciences biology Molecular Structure Chemistry Chinese hamster ovary cell biology.organism_classification Orexin receptor 0104 chemical sciences 010404 medicinal & biomolecular chemistry Docking (molecular) Area Under Curve Drug Design Molecular Medicine Orexin Receptor Antagonists Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 63(19) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The orexin receptors are peptide-sensing G protein-coupled receptors that are intimately linked with regulation of the sleep/wake cycle. We used a recently solved X-ray structure of the orexin receptor subtype 2 in computational docking calculations with the aim to identify additional ligands with unprecedented chemotypes. We found validated ligands with a high hit rate of 29% out of those tested, none of them showing selectivity with respect to the orexin receptor subtype 1. Furthermore, of the higher-affinity compounds examined, none showed any agonist activity. While novel chemical structures can thus be found, selectivity is a challenge owing to the largely identical binding pockets. |
| Databáze: | OpenAIRE |
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