Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor
Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor
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DOI：
10.1021/acs.jmedchem.6b01148
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发表时间：
2017-01-26
影响因子：
7.3
通讯作者：
Shi, Lei
中科院分区：
文献类型：
--
作者：
Michino, Mayako;Boateng, Comfort A.;Shi, Lei
多巴胺D-3受体（D3 R）部分激动剂和拮抗剂都被认为是治疗物质使用障碍的潜在药物。与拮抗剂相比，部分激动剂可能引起较少的副作用，因为它们维持一些多巴胺能张力，并且可能对正常神经元功能的破坏性较小。在这里，我们报告了三组4-苯基哌嗪立体异构体，它们在功效上有很大差异：（R）-对映体是拮抗剂/弱部分激动剂，而（S）-对映体更有效。为了研究部分激动作用的结构基础，我们进行了比较微秒尺度的分子动力学模拟，从非活性状态的D3 R与这些对映体的复合物开始。模拟结果的分析揭示了由结合的（S）-对映体诱导的配体结合位点附近的常见结构重排，但不是由（R）-对映体诱导的，这是部分活化的受体构象的特征。这些与部分激动剂结合的受体模型可用于具有定制功效特征的化合物的基于结构的设计。
Both dopamine D-3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.