物理化学学报 >> 2005, Vol. 21 >> Issue (03): 333-337.doi: 10.3866/PKU.WHXB20050322

研究简报 上一篇    下一篇

磺胺基羟肟酸类HDAC抑制剂三维定量构效关系

刘冰; 陆爱军; 廖晨钟; 刘海波; 周家驹   

  1. 中国科学院过程工程研究所生化工程国家重点实验室,北京 100080; 中国科学院研究生院,北京 100039
  • 收稿日期:2004-08-18 修回日期:2004-10-09 发布日期:2005-03-15
  • 通讯作者: 周家驹 E-mail:jjzhou@home.ipe.ac.cn

3D-QSAR of Sulfonamide Hydroxamic Acid HDAC Inhibitors

LIU Bing; LU Ai-Jun; LIAO Chen-Zhong; LIU Hai-Bo; ZHOU Jia-Ju   

  1. State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100080; Graduate School of the Chinese Academy of Sciences, Beijing 100039
  • Received:2004-08-18 Revised:2004-10-09 Published:2005-03-15
  • Contact: ZHOU Jia-Ju E-mail:jjzhou@home.ipe.ac.cn

摘要: 组蛋白去乙酰化酶(HDAC)对染色质分布和基因调节起着重要的作用,也是治疗癌症和其它疾病的新靶点.羟肟酸类抑制剂是目前研究最多的组蛋白去乙酰化酶抑制剂.应用比较分子力场(CoMFA)法对一系列磺胺基羟肟酸类HDAC抑制剂进行了结构活性关系研究,得到的模型具有较高的交叉验证系数(q2=0.704).并在此基础上,建立了非交叉验证的偏最小二乘分析(PLS)模型.用该模型对随机选择的6个化合物组成的测试集进行了预测,得到了令人满意的结果,所建模型具有良好的预测能力.本研究对于设计高活性的HDAC抑制剂及抗癌药物都有指导意义.

关键词: 3D-QSAR, 比较分子力场, 组蛋白去乙酰化酶, 磺胺基羟肟酸, 分子对接

Abstract: Histone deacetylase (HDAC) greatly affects the chromatin topology and gene expression, and HDAC can be a new strategy in human cancer or tumour therapy. Hydroxamic acid compounds are component of most of the HDAC inhibitors. Studies on quantitative structure-activity relationship (QSAR) with CoMFA for the bioactivities of a series of sulfonamide hydroxamic acid HDAC inhibitors were carried out successfully, and a good cross-validated correlation (q2=0.704) was obtained .The non-cross-validated partial least squares (PLS) model was also well built and analyzed by the prediction of the active data CoMFA steric, and electrostatic contours. The results show that steric field (0.697) plays a more important role in increasing bioactivity than that of electrostatic field (0.303), and the R5 position prefers a larger group, but the R1 position prefers a smaller group.

Key words: 3D-QSAR, CoMFA, Histone deacetylase, Sulfonamide hydroxamic acid,  Autodock