Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands.
Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands.
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氟哌啶醇结合的 D-2 多巴胺受体结构激发了亚型选择性配体的发现
DOI：
10.1038/s41467-020-14884-y
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发表时间：
2020-02-26
影响因子：
16.6
通讯作者：
Wang, Sheng
中科院分区：
文献类型：
--
作者：
Fan, Luyu;Tan, Liang;Wang, Sheng
D2多巴胺受体（DRD2）是神经精神和内分泌疾病最成熟的治疗靶点之一。大多数临床批准和研究药物靶向这种受体是已知的亚家族选择性的所有三个D2样受体，而不是亚型选择性的DRD2。在这里，我们报告了与最常用的抗精神病药物氟哌啶醇结合的DRD 2的晶体结构。这些结构表明DRD2的延伸结合口袋将其与其他D2样亚型区分开来。结构的详细分析阐明了DRD2激活和亚型选择性所必需的关键结构决定因素。基于结构和机制驱动的筛选与先导物优化方法相结合产生了DRD2高选择性激动剂，其可用作研究DRD2生理和病理功能的化学探针以及无混杂性的有前途的治疗先导物。
The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Most clinically approved and investigational drugs that target this receptor are known to be subfamily-selective for all three D2-like receptors, rather than subtype-selective for only DRD2. Here, we report the crystal structure of DRD2 bound to the most commonly used antipsychotic drug,haloperidol. The structures suggest an extended binding pocket for DRD2 that distinguishes it from other D2-like subtypes. A detailed analysis of the structures illuminates key structural determinants essential for DRD2 activation and subtype selectivity. A structure-based and mechanism-driven screening combined with a lead optimization approach yield DRD2 highly selective agonists, which could be used as chemical probes for studying the physiological and pathological functions of DRD2 as well as promising therapeutic leads devoid of promiscuity.