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

J Med Chem. 2020 Feb 27;63(4):1528-1543. doi: 10.1021/acs.jmedchem.9b01787. Epub 2020 Jan 19.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Orexin Receptor Antagonists / chemistry
  • Orexin Receptor Antagonists / metabolism*
  • Orexin Receptors / chemistry
  • Orexin Receptors / metabolism*


  • HCRTR1 protein, human
  • HCRTR2 protein, human
  • Ligands
  • Orexin Receptor Antagonists
  • Orexin Receptors