物理化学学报 >> 2009, Vol. 25 >> Issue (04): 747-751.doi: 10.3866/PKU.WHXB200904281

研究论文 上一篇    下一篇

原子类型电拓扑状态指数预测吲哚喹唑啉衍生物的抗癌性

梅虎 刘丽 杨力 李建 闫宁 王琴   

  1. 重庆大学生物工程学院, 重庆 400044
  • 收稿日期:2008-10-12 修回日期:2008-12-09 发布日期:2009-03-31
  • 通讯作者: 梅虎 E-mail:meihu@cqu.edu.cn

Prediction of Antitumor Activities of Indolo[1,2-b]Quinazoline Derivatives Using Electrotopological State Indices for AtomTypes

 MEI Hu, LIU Li, YANG Li, LI Jian, YAN Ning, WANG Qin   

  1. College of Bioengineering, Chongqing University, Chongqing 400044, P. R. China
  • Received:2008-10-12 Revised:2008-12-09 Published:2009-03-31
  • Contact: MEI Hu E-mail:meihu@cqu.edu.cn

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摘要： 采用原子类型电拓扑状态指数(ETSIAT)对17个吲哚喹唑啉衍生物的抗癌活性进行定量构效关系(QSAR)的研究. 经逐步回归变量筛选, 得到包含4个ETSIAT变量的最优偏最小二乘模型, 其复决定系数R2、留一法交互验证复决定系数Q2和均方根误差RMSEE分别为0.806、0.736 和0.248. 将样本随机分为训练集和预测集后, 采用相同变量组合对模型进行外部验证, 结果显示模型具有较高的外部预测能力. 模型分析结果显示, 与抗癌活性相关的4个ETSIAT描述子对应结构碎片分别为≥N=, —NH—, =O, >N—. 其中—NH—结构碎片与抗癌活性呈负相关关系, 而≥N=, >N—和=O则与抗癌活性呈正相关关系. 此外, 研究亦显示, 取代基R1上存在强的吸电子基团可显著提高化合物的抗癌活性, 且影响抗癌活性的因素可能还有R2基团的空间位阻效应. 据此设计出4个化合物的预测活性比最高活性样本分别提高7.7%、15.3%、23.1%和130%.

关键词: 原子类型电拓扑状态指数, 吲哚喹唑啉衍生物, 抗癌, 定量构效关系, 偏最小二乘模型

Abstract: Electrotopological state indices for atomtype (ETSIAT)were employed to establish a quantitative structure- activity relationship (QSAR) model of antitumor activity for 17 indolo[1,2-b]quinazoline derivatives. Using step-wise regression analysis combined with the partial least squares (PLS) method, the coefficient of multiple determination R2, cross-validated coefficient of multiple determination Q2 (leave-one-out, LOO) and the root mean square error of estimation (RMSEE) of the optimal QSAR model were 0.806, 0.736, and 0.248, respectively. This optimal model was further validated by external validation. Results showed that 4 structural fragments, i.e., ≥N=, —NH—, =O, and >N— were closely correlated with the antitumor activities of indol[1,2-b]quinazoline derivatives. Furthermore, the structural fragment —NH— was negatively correlated with the antitumor activity while ≥N=, >N—, and =O were positively correlated with the antitumor activity. The substitution of R1 by strong electron-withdrawing groups may enhance compound antitumor activity and the steric effect at R2 may play an important role in the regulation of these activities. Based on the above observations, a total of 9 molecules were designed and predicted by using the optimal PLS model. Predicted activities of 4 molecules were 7.7%, 15.3%, 23.1%, and 130%higher than that of sample 13, respectively.

Key words: Electrotopological state indices for atomtype, Indolo[1,2-b]quinazoline derivative, Antitumor, Quantitative structure-activity relationship, Partial least squares model