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.
Highlights
The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders
These include the Merck compound L-741626, which shows around 10-fold DRD2 versus DRD3/ DRD4 selectivity in radioligand-binding assays (Fig. 1a)
On the other hand, since the distance between extended binding pocket (EBP) and orthostericbinding pockets (OBPs) is longer in DRD3 than in DRD2 (SEBP-OBP) and DRD4 (EBP-OBP)[16,35], highly DRD3selective compounds, such as R-2216,35, can be obtained by designing compounds with a longer linker between the OBPbinding moiety and EBP-binding moiety
Summary
The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Owing to the identification of the unique rigid extended binding pocket (EBP) for each receptor, several DRD3-selective and DRD4-selective ligands have been identified via SBDD in the last few years[12,13,14]. The success rate of SBDD is much lower if the target binding pocket is not rigid[17], just like the DRD2 EBP. To address this problem, we solve here the complex structure of the DRD2 bound to a commonly used typical antipsychotic drug-haloperidol. Driven by our structural delineation of the unique ligand-binding pose at DRD2 and activation mechanism via SEBP and OBP, we further obtain two DRD2 subtype-selective agonists—O4SE6 and O8LE6, excluding agonism at DRD3 and DRD4
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