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化学学报
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化学学报 ›› 2004, Vol. 62 ›› Issue (16): 1544-1550. 上一篇    下一篇

研究论文

PPAR激动剂的定向设计、虚拟筛选及合成

冯君, 郭彦伸, 陆颖, 郭宗儒   

  1. 中国医学科学院, 北京协和医科大学药物研究所, 北京, 100050
  • 投稿日期:2003-11-05 修回日期:2004-02-13 发布日期:2014-02-17
  • 通讯作者: zrguo@imm.ac.cn
  • 作者简介:郭宗儒:E-mail:zrguo@imm.ac.cn
  • 基金资助:
    北京市自然科学基金(No.7022026)和教育部博士点基金(No.20020023032)资助项目.

Design, Virtual Screening and Synthesis of PPAR Agonists

FENG Jun, GUO Yan-Shen, LU Ying, GUO Zong-Ru   

  1. Institute of Material Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050
  • Received:2003-11-05 Revised:2004-02-13 Published:2014-02-17

PDF

990

被引次数

53

过氧化物酶体增殖因子活化受体(PPAR)是核受体超家族的一员.基于受体结构的药物分子设计与组合化学策略相结合,构建了过氧化物酶体增殖因子活化受体(PPAR)激动剂的虚拟化合物库.将已知小分子配体(GW409544)与PPAR晶体复合物进行剥离,得到受体的活性构象,并利用此活性受体分子与虚拟库中小分子进行对接和虚拟筛选,得到理论上结合较强的化合物,并对这些化合物进行合成,共合成9个新化合物.活性筛选结果显示化合物对PPAR具有一定的亲和力,其中有三个化合物显示出对PPARα,PPARγ的双重激动作用,从而指导新活性化合物的设计和合成.

关键词: PPAR激动剂, 虚拟筛选, DOCK

The PPARs are members of the nuclear hormone receptor super family.A novel virtual library of PPAR agonists by structure-based drug design and combinatorial library method was described.The PPAR-LBD 3D model used for virtual screening was built by the 1K74 and 1K7l crystal structure.After DOCK program screening, which automatically simulated the interaction between the ligands and receptors, the strong-binding virtual compounds were selected and synthesized.Nine new compounds have been synthesized.Three of them exhibitpotent dual PPARα/γ agonist activity as demonstrated by in vitro binding.The activity data offered detailed molecular information for design and synthesis of new compounds.

Key words: PPAR agonist, virtual screening, DOCK