A Novel Cryo-EM Structure Enables Development of Selective Cannabinoid Receptor Drugs.
A Novel Cryo-EM Structure Enables Development of Selective Cannabinoid Receptor Drugs.
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新型冷冻电镜结构可实现选择性大麻素受体药物的开发。
DOI：
10.1021/acs.biochem.0c00263
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发表时间：
2020
期刊：
影响因子：
2.9
通讯作者：
Wacker,Daniel
中科院分区：
文献类型：
--
作者：
Zilberg,Gregory;Wacker,Daniel
随着世界各国逐渐认识到大麻的治疗潜力，我们才刚刚开始了解其合成的不同化合物（恰当地命名为大麻素）的复杂药理学。然而，有一点是肯定的：医用大麻的合法化表明大麻素系统可用于治疗多种疾病，包括癫痫、神经性疼痛和肥胖症。信号系统的中心是 G 蛋白偶联受体 (GPCR) 蛋白家族的两个成员，即 1 型和 2 型大麻素受体，分别称为 CB1 和 CB2。 CB1 已被发现介导大麻素的大部分神经效应，例如四氢大麻酚 (Δ9-THC) 臭名昭著的精神作用。由于 CB1 介导的有害神经副作用，许多以大麻素为灵感的药物开发工作都失败了。另一方面，CB2 主要在免疫细胞和周围神经系统中表达，使其成为 CB1 的诱人替代靶点。具体来说，选择性靶向 CB2 可能会赋予现有非选择性大麻素的镇痛和抗癫痫特性，而不会出现 JWH-018（“Spice”）等合成完全激动剂所出现的神经精神不良靶向副作用。 1 然而，设计具有所需生理效应的 CB2 选择性药物的一个主要障碍是对 (a) CB2 如何被配体激活以及 (b) CB1 和 CB2 之间的药理学差异的机制理解很差。这在很大程度上是由于缺乏有关 CB2 的结构信息。 2 在《Cell》最近发表的一篇令人兴奋的文章中，3 Xing 等人。结合冷冻电镜研究和计算方法，不仅可以揭示 CB2 活化和配体选择性的分子方面，而且可以在基于结构的有效 CB2 选择性化合物的设计中利用其数据（图 1）。本次研究的核心内容是 CB2 与异源三聚体 Gi 蛋白复合并与强效 CB1/CB2 激动剂 WIN 55,212-2 结合的 3.2 Å 冷冻电镜结构。为了阐明激动剂和拮抗剂如何与受体不同地相互作用以分别激活和抑制信号传导，作者开发了一种创新的计算方法。基于配体-受体相互作用的相对能量贡献的计算，F1173。 36，W1945。 43 和 W2586。 48 种被鉴定为与激动剂 WIN 55,212-2 和之前报道的拮抗剂 AM10257 存在差异相互作用。 4 表明与
As countries worldwide are slowly adapting to recognize the therapeutic potential of cannabis, we are just beginning to understand the complex pharmacology of the different compounds it synthesizes, aptly named cannabinoids. One thing, however, is certain: the legalization of medical cannabis showcases the targeting of the cannabinoid system for the treatment of a variety of conditions, including epilepsy, neuropathic pain, and obesity. At the center of the signaling system are two members of the family of proteins known as G protein-coupled receptors (GPCRs), cannabinoid receptors type 1 and 2, termed CB1 and CB2, respectively. CB1 has been found to mediate the majority of neurological effects of cannabinoids, such as the infamous psychoactive effects of tetrahydrocannabinol (Δ9-THC). Many cannabinoid-inspired drug development efforts have failed due to CB1-mediated deleterious neurological side effects. CB2, on the other hand, is predominantly expressed in immune cells and in the peripheral nervous system, making it an alluring alternative target to CB1. Specifically, selective targeting of CB2 might confer the analgesic and antiepileptic properties of existing nonselective cannabinoids without the neuropsychiatric adverse on-target side effects seen with synthetic full agonists such as JWH-018 (“Spice”). 1A key obstacle to designing CB2-selective medications with desired physiological effects, however, has been a poor mechanistic understanding of both (a) how CB2 is activated by ligands and (b) the pharmacological differences between CB1 and CB2. This was in no small part due to the lack of structural information about CB2. 2 In an exciting recent publication in Cell, 3 Xing et al. combined cryo-EM studies and computational approaches not only to reveal molecular aspects of CB2 activation and ligand selectivity but also to leverage their data in the structure-based design of potent, CB2-selective compounds (Figure 1). A centerpiece of the presented work is the 3.2 Å cryo-EM structure of CB2 in complex with the heterotrimeric Gi protein and bound to the potent CB1/CB2 agonist WIN 55,212-2. To shed light on how agonists and antagonists differentially interact with the receptor to activate and inhibit signaling, respectively, the authors developed an innovative computational approach. On the basis of the calculation of relative energy contributions of ligand− receptor interactions, F1173. 36, W1945. 43, and W2586. 48 were identified as differentially interacting with the agonist WIN 55,212-2 and the previously reported antagonist AM10257. 4 To show that interactions with