物理化学学报 >> 2008, Vol. 24 >> Issue (12): 2249-2256.doi: 10.3866/PKU.WHXB20081217

研究论文 上一篇    下一篇

胆固醇酯转运蛋白抑制剂的3D-QSAR模型

颜琳芳, 胡桂香, 徐晶, 赵文娜, 俞庆森   

  1. 浙江大学宁波理工学院分子设计与营养工程市重点实验室, 浙江 宁波 315100
  • 收稿日期:2008-07-08 修回日期:2008-10-08 发布日期:2008-12-04
  • 通讯作者: 胡桂香 E-mail:hugx@nit.zju.edu.cn

3D-QSAR Models on Cholesteryl Ester Transfer Protein Inhibitors

YAN Lin-Fang, HU Gui-Xiang, XU Jing, ZHAO Wen-Na, YU Qing-Sen   

  1. Key Laboratory for Molecular Design and Nutrition Engineering of Ningbo City, Ningbo Institute of Technology, Zhejiang University, Ningbo 315100, Zhejiang Province, P. R. China
  • Received:2008-07-08 Revised:2008-10-08 Published:2008-12-04
  • Contact: HU Gui-Xiang E-mail:hugx@nit.zju.edu.cn

摘要: 利用VolSurf参数和比较分子场分析(CoMFA)方法对N,N-二取代三氟-3-氨基-2-丙醇衍生物类胆固醇酯转运蛋白抑制剂进行了三维定量构效关系(3D-QSAR)模型研究, 均得到较好的结果, 训练集模型具有良好的预测能力. VolSurf参数分析表明抑制活性高的分子必须具有合适的亲水性、多的氢键给体和少的氢键受体; 在一定范围内, 分子量大、表面光滑且非球性高的分子抑制活性高; 高疏水性以及质量中心与疏水区中心的高不平衡性对活性是不利因素. CoMFA结果表明, 立体作用对活性的影响较静电作用稍强, N-苯基取代基苯氧基的间位体积大且正电性强的基团对活性有利, N-苄基取代基的间位体积大且合适的电负性对活性有利, 而苄基的对位立体位阻的增加则对活性不利. VolSurf参数提供了分子整体性质信息, CoMFA提供了取代基信息, 两者互为补充, 对该类抑制剂新化合物的设计具有指导意义.

关键词: 胆固醇酯转运蛋白, 抑制剂, VolSurf, CoMFA, 3D-QSAR

Abstract: A three dimensional-quantitative structure activity relationship (3D-QSAR) study was performed on a series of CETP inhibitors N,N-disubstituted trifluoro-3-amino-2-propanol derivatives using VolSurf descriptors and the comparative molecular field analysis (CoMFA) method. Good results were obtained and the training set was predictable for the test set. VolSurf descriptor analysis showed that suitable hydrophilicity, more hydrogen bond donors and less acceptor were favorable to activity. To some extent, high molecular weight, a smooth surface and high non-globularity were also beneficial to activity. High hydrophobicity and an imbalance between the center of mass and the barycentre of its hydrophobic regions decreased the activity. The result of CoMFA demonstrated that the activity was influenced more by steric effect than electrostatic effect. At the phenoxy meta position in the N-phenyl substituent, groups that have a large volume and strong positive electricity increase the activity. At the meta position of the N-benzyl substituent, groups that have a large volume and suitable electronegativity were beneficial to activity. At the para position of the benzyl group, a large steric effect was detrimental to activity. VolSurf descriptors provided the integral property information of the molecules and CoMFA gave information on substituents. Both methods complemented each other, which can provide assistance to the design of new compounds belonging to this class of inhibitors.

Key words: Cholesteryl ester transfer protein (CETP, Inhibitor, VolSurf, CoMFA, 3D-QSAR

MSC2000: 

  • O641