Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D₂ dopamine receptor (D₂R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D₂R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D₂R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D₂R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and β-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated β-arrestin recruitment (EC₅₀ = 320 nM, E_max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.

中文翻译：

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虚拟化学文库中功能选择性D ₂多巴胺受体配体的结构指导筛选

功能选择性配体稳定诱导用于信令的偏好G蛋白偶联受体（GPCR）的构象通过由内源性激动剂激活胞内途径的子集。微调受体功能活性的可能性为开发药物提供了机会，这些药物可以通过与治疗作用相关的途径选择性地发出信号，并避免那些引起副作用的途径。动物研究表明，在D ₂多巴胺受体（D ₂ R）上显示功能选择性的配体可能是更安全有效的抗神经精神疾病药物。在这项工作中，功能选择D _2的计算设计使用基于结构的虚拟筛选探索R配体。已知的功能选择性配体与D ₂ R同源性模型的分子对接表明，此类化合物通过与正构位点的相互作用而锚定，并延伸到共同的第二个口袋中。定制的虚拟文库与D ₂停靠在一起，该虚拟文库将近13000个带有2,3-二氯苯基哌嗪（一种特有的正构支架）的化合物，该化合物通过连接器连接到各种化学部分，是一种特有的正构支架。R模型。合成了18个占据正构和变构位点的顶级化合物，从而发现了16个部分激动剂。大多数配体在G蛋白和β-arrestin募集试验中具有可比的最大作用，但有一部分显示出对单途径的偏爱。特别是，化合物4刺激了β-arrestin募集（EC ₅₀ = 320 nM，E _max = 16％），但没有可检测的G蛋白信号传导。将讨论使用基于结构的筛选和虚拟文库来发现具有定制功能特性的GPCR配体。