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

Rappas, Mathieu; Ali, Ammar A. E.; Bennett, Kirstie A.; Brown, Jason D.; Bucknell, Sarah J.; Congreve, Miles; Cooke, Robert M.; Cseke, Gabriella; de Graaf, Chris; Doré, Andrew S.; Errey, James C.; Jazayeri, Ali; Marshall, Fiona H.; Mason, Jonathan S.; Mould, Richard; Patel, Jayesh C.; Tehan, Benjamin G.; Weir, Malcolm; Christopher, John A.

doi:10.1021/acs.jmedchem.9b01787.s001

jm9b01787_si_001.pdf (169.67 kB)

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

journal contribution

posted on 2020-01-19, 13:03 authored by Mathieu Rappas, Ammar A. E. Ali, Kirstie A. Bennett, Jason D. Brown, Sarah J. Bucknell, Miles Congreve, Robert M. Cooke, Gabriella Cseke, Chris de Graaf, Andrew S. Doré, James C. Errey, Ali Jazayeri, Fiona H. Marshall, Jonathan S. Mason, Richard Mould, Jayesh C. Patel, Benjamin G. Tehan, Malcolm Weir, John A. Christopher

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.