CHISHIKI

Drug Discovery

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

By Mathieu Rappas, Ammar Ali, Kirstie Bennett, Jason Brown, Sarah Bucknell, Miles Congreve, Robert Cooke, Gabriella Cseke, Chris de Graaf, Andrew Doré, James Errey, Ali Jazayeri, Fiona Marshall, Jonathan Mason, Richard Mould, Jayesh Patel, Benjamin Tehan, Ma | Dec 22, 2019

Summary

Mathieu Rappas, Head of Protein Expression and Biochemistry at Sosei Heptares, together with fellow scientists, recently published a Featured Article titled “Comparison of orexin 1 and orexin 2 ligand binding modes using X-ray crystallography and computational analysis” in the renowned Journal of Medicinal Chemistry. In the paper he presents X-ray structures of the orexin receptors in complex with ten new antagonist ligands from diverse chemotypes and discusses how selectivity between OX1 and OX2 can be achieved.

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.

Keywords

Orexin, OX-A, OX-B, SBDD, DORA, 1-SORA, 2-SORA

Acknowledgements

Research reported in this paper was supported by the National Institute on Drug Addiction of the National Institutes of Health under award number R01DA039553.

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