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

By Mathieu Rappas et al. | Dec 22, 2019

サマリー

当社医薬品化学チームのディレクターであるJohn Christopher博士が、当社研究員との共著で、"Comparison of orexin 1 and orexin 2 ligand binding modes using X-ray crystallography and computational analysis"と題したFeatured ArticleをJournal of Medicinal Chemistry誌で発表しました。本稿では、異なる化学種の新たな10つの拮抗薬(リガンド)と複合するオレキシン受容体のX線構造を示すと共に、OX1とOX2間においてどの程度の選択性を実現できるかについて論じています。

概要

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

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