Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.,Journal of Medicinal Chemistry

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Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-19 , DOI: 10.1021/acs.jmedchem.9b01787
Mathieu Rappas ₁ , Ammar A E Ali ₁ , Kirstie A Bennett ₁ , Jason D Brown ₁ , Sarah J Bucknell ₁ , Miles Congreve ₁ , Robert M Cooke ₁ , Gabriella Cseke ₁ , Chris de Graaf ₁ , Andrew S Doré ₁ , James C Errey ₁ , Ali Jazayeri ₁ , Fiona H Marshall ₁ , Jonathan S Mason ₁ , Richard Mould ₁ , Jayesh C Patel ₁ , Benjamin G Tehan ₁ , Malcolm Weir ₁ , John A Christopher ₁

Affiliation

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.

中文翻译：

使用 X 射线晶体学和计算分析比较 Orexin 1 和 Orexin 2 配体结合模式。

食欲素系统由两个 G 蛋白偶联受体 OX1 和 OX2 组成，由神经肽 OX-A 和 OX-B 激活，被牢固地确立为行为唤醒、睡眠和觉醒的关键调节因子，并且一直是一个领域过去二十年的大量研究工作。展示了与来自不同化学型的 10 种新拮抗剂配体复合的受体的 X 射线结构，这补充了系统的现有结构信息，并强调了亲脂性热点和水分子对于这些肽能 GPCR 靶标的至关重要性。讨论了从关于药效团模型的实用性的结构信息以及如何实现 OX1 和 OX2 之间的选择性的知识。

更新日期：2020-01-21

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