Comparison of orexin 1 and orexin 2 ligand binding modes using X-ray crystallography and computational analysis

DOI: 10.1021/acs.jmedchem.9b01787

Authors: Mathieu Rappas (Sosei Heptares) , Ammar Ali (Sosei Heptares) , Kirstie A. Bennett (Sosei Heptares) , Jason D. Brown (Sosei Heptares) , Sarah J. Bucknell (Sosei Heptares) , Miles Congreve (Sosei Heptares) , Robert M. Cooke (Sosei Heptares) , Gabriella Cseke (Sosei Heptares) , Chris De Graaf (Sosei Heptares) , Andrew S. Dore (Sosei Heptares) , James C. Errey (Sosei Heptares) , Ali Jazayeri (Sosei Heptares) , Fiona H. Marshall (Sosei Heptares) , Jonathan S. Mason (Sosei Heptares) , Richard Mould (Sosei Heptares) , Jayesh C. Patel (Sosei Heptares) , Benjamin G. Tehan (Sosei Heptares) , Malcolm Weir (Sosei Heptares) , John A. Christopher (Sosei Heptares)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 5788 , 20025 , 12425 , 5999 , 5788 , 17185 , 20025

Abstract: 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 behavioural 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 ten 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.

Journal Keywords: Orexin; OX-A; OX-B; SBDD; DORA; 1-SORA; 2-SORA

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: Swiss Light Source beamline X06SA

Added On: 06/01/2020 10:57

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)