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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)11045-11053
Number of pages9
JournalJournal of Medicinal Chemistry
Volume63
Issue number19
DOIs
StatePublished - Oct 8 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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