吡唑类转化生长因子-β受体激酶抑制剂的定量构效关系研究

Study on Quantitative Structure–Activity Relationship of Pyrazole-based Inhibitors of the Transformation Growth Factor-β Type Ⅰ Receptor Kinase Domain

用分子力学、分子模拟退火动力学、量子化学等方法对转化生长因子-β受体激酶(TβR-Ⅰ)的取代吡唑类抑制剂进行了结构优化.用遗传算法(GFA)并结合多元线性回归方法(MLR),对该类抑制剂进行了定量构效关系研究,筛选出了影响抑制剂活性的主要因素,建立了定量构效关系方程(QSAR).结果表明,分子的总偶极矩的Y分量的平方(μy)2、分子中喹啉环上的氮原子的净电荷QN3、Jurs的相对负电荷表面积RNCS描述等是影响该类化合物抑制活性的主要因素.所得模型对该类化合物关于TβR-Ⅰ的抑制活性有较好的预测效果(R2=0.834,Rcv2=0.575,s=0.243,F=13.439).

The geometry structure of pyrazole-based inhibitors of the transformation growth factor-β type I receptor kinase domain （TβR- Ⅰ ） was optimized by means of quantum chemistry, molecular mechanism and molecular anneal dynamics. The quantitative structure-activity relationship of these inhibitors in regard to TβR- Ⅰ was systematically studied using the genetic function approximation（GFA） and multiple linear regression（MLR）. Some main independent factors affecting the activity of the compounds were selected out, and then the QSAR equation was established. It has found that the square of y component of total dipole moment of molecule（μy）2, the net charge of the nitrogen atom of quinolin QN3, and Jurs descriptor RNCS-- Relative negative charge surface area, are the main independent factors contributing to the inhibiting activity of the compounds. The fitting correlation coefficient R^2, the cross-validation Rcv^2,the standard error of the regression model s and F test value F for the model established by this study are, 0.834, 0.576, 0.243 and 13.439, respectively. The results suggest that this model has good predictability.