Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor

Gunera, Jakub; Baker, Jillian G.; van Hilten, Niek; Rosenbaum, Daniel M.; Kolb, Peter

Abstract

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.

Citation

Gunera, J., Baker, J. G., van Hilten, N., Rosenbaum, D. M., & Kolb, P. (2020). Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor. Journal of Medicinal Chemistry, 63(19), 11045-11053. https://doi.org/10.1021/acs.jmedchem.0c00964

• Journal Article Type: Article
• Acceptance Date: Sep 14, 2020
• Online Publication Date: Sep 25, 2020
• Publication Date: Oct 8, 2020
• Deposit Date: Oct 6, 2020
• Publicly Available Date: Sep 26, 2021
• Journal: Journal of medicinal chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 63
• Issue: 19
• Pages: 11045-11053
• DOI: https://doi.org/10.1021/acs.jmedchem.0c00964
• Keywords: Molecular Medicine; Drug Discovery
• Public URL: https://nottingham-repository.worktribe.com/output/4929977
• Publisher URL: https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.0c00964