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

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.