Beyond small-molecule SAR: using the dopamine D3 receptor crystal structure to guide drug design.
Beyond small-molecule SAR: using the dopamine D3 receptor crystal structure to guide drug design.
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DOI：
10.1016/b978-0-12-420118-7.00007-x
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Newman AH
中科院分区：
文献类型：
--
作者：
Keck TM;Burzynski C;Shi L;Newman AH
多巴胺D3受体是多种神经疾病的药物治疗靶点，包括精神分裂症、不宁腿综合征和药物成瘾。D3和D2受体之间的高蛋白序列同源性给在体内开发D3受体选择性配体带来了挑战，这些配体的行为行为可以归因于D3受体的参与。然而，在过去的二十年里，通过对小分子构效关系(SAR)的研究，人们发现了各种各样的化学支架，从而产生了几种具有高亲和力和体内活性的D3受体选择性配体。然而，可行的临床候选药物仍然有限。最近对D3受体高分辨率晶体结构的测定为基于结构的药物设计注入了活力，为受体-配体相互作用的分子动力学模型和可测试预测提供了改进。这篇综述将重点介绍最近的临床前和临床研究，显示D3受体选择性配体在治疗成瘾方面的潜在效用。此外，还考察了基于结构的合理的D3受体选择性配体的药物设计策略，这些策略补充了传统的小分子SAR以提高选择性和定向疗效。
The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small molecule structure-activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. This review will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small molecule SAR to improve the selectivity and directed efficacy profiles are examined.