ArticleProceedings of the National Academy of Sciences of the United States of America2020
Structure-based development of a subtype-selective orexin 1 receptor antagonist.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 53 citations in OpenAlex.
- In Silico to In Cerebro-Development of the Orexin Receptor Antagonist "Photorexant" for Photomodulation In Vitro and in Mouse Brains.Angewandte Chemie (International ed. in English) · 2026Article
- Selective modulation of orexinergic receptors by neem-derived phytochemicals: Computational analysis of structure-activity relationships.Toxicology reports · 2025Article
- Structural insights into GPCR signaling activated by peptide ligands: from molecular mechanism to therapeutic application.Experimental & molecular medicine · 2025Review
- Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediatedEJNMMI research · 2024Article
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- G Protein-Coupled Receptor-Ligand Pose and Functional Class Prediction.International journal of molecular sciences · 2024Article
- Prediction of adverse events risk in patients with comorbid post-traumatic stress disorder and alcohol use disorder using electronic medical records by deep learning models.Drug and alcohol dependence · 2024Article
- Prediction of Adverse Events Risk in Patients with Comorbid Post- Traumatic Stress Disorder and Alcohol Use Disorder Using Electronic Medical Records by Deep Learning Models.Research square · 2023Article
- Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Constrained catecholamines gain βNature communications · 2023Article
- Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations.Nature and science of sleep · 2023Review
- Structure-based discovery of nonopioid analgesics acting through the αScience (New York, N.Y.) · 2022Article
- Molecular mechanism of the wake-promoting agent TAK-925.Nature communications · 2022Article
- Clinical, Genetic and Functional Characterization of a NovelJournal of personalized medicine · 2022Article
- Leveraging nonstructural data to predict structures and affinities of protein-ligand complexes.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The Novel Application of Geometric Morphometrics with Principal Component Analysis to Existing G Protein-Coupled Receptor (GPCR) Structures.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target.Molecules (Basel, Switzerland) · 2021Review
- Orexin receptors in GtoPdb v.2021.3.IUPHAR/BPS guide to pharmacology CITE · 2021Article
- Hypocretin/Orexin Receptor Pharmacology and Sleep Phases.Frontiers of neurology and neuroscience · 2021Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
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
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.