多巴胺D2受体的同源模建研究

Homology modeling of Dopamine D2 receptor

多巴胺是大脑中含量最丰富的儿茶酚胺类神经递质,主要通过多巴胺受体调控中枢神经系统的多种生理功能,其中多巴胺D2受体与药物成瘾、精神分裂症、帕金森病等多种疾病的发生相关。然而多巴胺D2受体的晶体结构至今尚未解析出来,给相关疾病的药物设计与开发带来困难。本文采用同源模建的方法,用目前与多巴胺D2受体同源性最高的多巴胺D3受体(3PBL)作为模板,构建多巴胺D2受体的三维结构。经过优化和分子动力学模拟,用Profile-3D和Ramachandran plot对模型进行评估,然后用多巴胺D2受体拮抗剂千金藤啶碱(stepholidine,SPD)进行对接验证,证明构建的多巴胺D2受体模型合理、可靠。

Dopamine（DA） is the most abundant catecholaminergic neurotransmitter in the brain.It controls a variety of physiological functions of the central nervous system by Dopamine receptor, and Dopamine D2 receptor has been associated with a variety of neuropathological diseases, such as drug addiction, schizophrenia, Parkinson＇s disease. But so far, the structure of Dopamine D2 receptor is not available, which limited the design and development of relevent drugs. In this paper, the homology model of Dopamine D2 receptor was developed by using the Dopamine D3 receptor （3PBL） as template, which has the highest sequence identity to D2 receptor. After Optimization and molecular dynamics simulation, the refined model structure was obtained. The fmal refined model was assessed by Profile-3D and Ramachandran plot programs, then verified by docking with stepholidine（SPD）. The results show that the Dopamine D2 model which we built is reasonable and reliable.