Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X‑ray Crystallography and Computational Analysis

The orexin system, which consists
of the two G protein-coupled
receptors OX1 and OX2, activated by the neuropeptides
OX-A and OX-B, is firmly established as a key regulator of behavioral
arousal, sleep, and wakefulness and has been an area of intense research
effort over the past two decades. X-ray structures of the receptors
in complex with 10 new antagonist ligands from diverse chemotypes
are presented, which complement the existing structural information
for the system and highlight the critical importance of lipophilic
hotspots and water molecules for these peptidergic GPCR targets. Learnings
from the structural information regarding the utility of pharmacophore
models and how selectivity between OX1 and OX2 can be achieved are discussed.