Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor
Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor
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DOI：
10.1016/j.str.2022.11.001
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发表时间：
2022-12-01
期刊：
影响因子：
5.7
通讯作者：
Iwata, So
中科院分区：
文献类型：
--
作者：
Asada, Hidetsugu;Im, Dohyun;Iwata, So
食欲素受体是一个G蛋白偶联受体家族，由两个亚型组成：食欲素-1受体(OX1Rs)和OX2Rs。它们在整个中枢神经系统都有表达，并参与调节睡眠-觉醒周期。食欲素受体拮抗剂的开发在药物发现中变得重要，因为这些受体的调节可以导致与睡眠和觉醒调节相关的疾病的新疗法，如失眠。在这项研究中，我们确定了OX2R与食欲素受体双拮抗剂(DORA)lemprexant结合的结构，分辨率为2.89埃。基于结构和模拟的DORAs的动力学和动力学性质的比较表明，分子与受体的结合热和分子内结构的熵是可以分别控制的。这些结果补充了现有的结构信息，并使我们能够讨论药效团模型的有用性和对OXRs的靶向选择性。
Orexin receptors are a family of G protein-coupled receptors that consist of two subtypes: orexin-1 receptors (OX1Rs) and OX2Rs. They are expressed throughout the central nervous system and are involved in regu-lating the sleep-wake cycle. The development of antagonists to orexin receptors has become important in drug discovery because modulation of these receptors can lead to novel treatments for diseases related to the regulation of sleep and wakefulness, such as insomnia. In this study, we determined that the structure of OX2R bound to lemborexant, a dual orexin receptor antagonist (DORA), at 2.89 angstrom resolution. Comparisons of kinetic and dynamic properties of DORAs based on structures and simulations suggest that the enthalpy of molecular binding to receptors and the entropy derived from intramolecular structure can be separately controlled. These results complement existing structural information and allow us to discuss the usefulness of pharmacophore models and target selectivity to OXRs.