高等学校化学学报

高等学校化学学报 ›› 2011, Vol. 32 ›› Issue (8): 1779.

• 研究论文 • 上一篇    下一篇

新型多巴胺D3受体抑制剂的发现

邓欣贤1, 沈庆1, 徐丽丽1, 熊子君1, 赵伟利1, 镇学初2, 付伟1   

  1. 1. 复旦大学药学院药物化学教研室, 智能化递药教育部和全军重点实验室, 上海 201203;
    2. 中国科学院上海药物研究所, 上海 201203
  • 收稿日期:2011-05-12 修回日期:2011-06-13 出版日期:2011-08-10 发布日期:2011-07-19
  • 通讯作者: 付伟 E-mail:weifu@gmail.com
  • 基金资助:

    国家自然科学基金(批准号: 20702009)、 国家“八六三”计划项目(批准号: 2009AA02Z308)和国家“九七三”计划项目(批准号: 2010CB912601)资助.

Discovery of a Novel Dopamine D3 Receptor Inhibitor

DENG Xin-Xian1, SHEN Qing1, XU Li-Li1, XIONG Zi-Jun1, ZHAO Wei-Li1, ZHEN Xue-Chu2, FU Wei1*   

  1. 1. Department of Medicinal Chemistry, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Fudan University, Shanghai 201203,  China;
    2. State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203,  China
  • Received:2011-05-12 Revised:2011-06-13 Online:2011-08-10 Published:2011-07-19
  • Contact: FU Wei E-mail:weifu@gmail.com
  • Supported by:

    国家自然科学基金(批准号: 20702009)、 国家“八六三”计划项目(批准号: 2009AA02Z308)和国家“九七三”计划项目(批准号: 2010CB912601)资助.

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摘要： 根据最新解析的多巴胺D3受体的晶体结构进行活性位点分析, 建立了基于受体的药效团模型, 并对Asinex Gold Collection 数据库进行筛选, 选择7个化合物进行生物活性测试, 得到了高活性新型多巴胺受体抑制剂(04932482), 它对多巴胺D3受体抑制率达85.45%, 其Ki值为(806.75±34.58) nmol/L. 进一步对活性化合物进行结构分析, 研究了其与受体相互作用的模式, 并以此为指导提出以04932482为先导化合物进行结构改造的方向.

关键词: 多巴胺D3受体, 药效团模型, 数据库筛选, 抑制剂

Abstract: Dopamine D3 receptor regulates the synthesis and release of dopamine in brain. It is implicated in many neurological processes, including motivation, pleasure, cognition, memory, learning, and fine motor control. It is involved in the pathology of psychotic diseases, such as schizophrenia, Parkinson's disease and drug addiction. It is of great significance to discover novel D3 inhibitors through pharmacophore-based virtual screening for the development of anti-psychotic drugs. In this study, we employed the latest discovered high-resolution crystal structure of human D3 receptor to conduct active-site-analysis, build the receptor-based pharmacophore model and screen the Asinex GOLD Collection database. 7 hits were purchased and tested by pharmacological experiments. A novel inhibitor 04932482 with a high activity against D3 receptor was obtained[Ki=(806.75±34.58) nmol/L]. The structure analysis was conducted and the ligand-receptor interaction was further investigated by docking to guide the structure modification and optimization of compound 04932482.

Key words: Dopamine D3 receptor, Pharmacophore model, Database screening, Inhibitor

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