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

Luyu Fan, Liang Tan, Zhangcheng Chen, Jianzhong Qi, Fen Nie, Zhipu Luo, Jianjun Cheng () and Sheng Wang ()
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Luyu Fan: University of Chinese Academy of Sciences
Liang Tan: ShanghaiTech University
Zhangcheng Chen: University of Chinese Academy of Sciences
Jianzhong Qi: University of Chinese Academy of Sciences
Fen Nie: University of Chinese Academy of Sciences
Zhipu Luo: Soochow University
Jianjun Cheng: ShanghaiTech University
Sheng Wang: University of Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14884-y

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