Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands

作者：Luyu Fan, Liang Tan, Zhangcheng Chen, Jianzhong Qi, Fen Nie, Zhipu Luo, Jianjun Cheng, Sheng Wang · 发表于：Nature Communications · 年份：2020 · DOI：10.1038/s41467-020-14884-y · 被引用次数：122 · 研究领域：Receptor Mechanisms and Signaling、Pharmacological Receptor Mechanisms and Effects、Neuropeptides and Animal Physiology

Abstract The D 2 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 D 2 -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 D 2 -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.