Chemical Laboratory, Central Leather Research Institute, Council of Scientific and Industrial Research, Adyar, Chennai 600 020, India.
Chem Biol Drug Des. 2012 Jun;79(6):935-42. doi: 10.1111/j.1747-0285.2012.01351.x. Epub 2012 Mar 19.
Three-dimensional quantitative structure activity relationship (3D-QSAR) study has been carried out on the Escherichia coli DHFR inhibitors 2,4-diamino-5-(substituted-benzyl)pyrimidine derivatives to understand the structural features responsible for the improved potency. To construct highly predictive 3D-QSAR models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used. The predicted models show statistically significant cross-validated and non-cross-validated correlation coefficient of r2 CV and r2 nCV, respectively. The final 3D-QSAR models were validated using structurally diverse test set compounds. Analysis of the contour maps generated from CoMFA and CoMSIA methods reveals that the substitution of electronegative groups at the first and second position along with electropositive group at the third position of R2 substitution significantly increases the potency of the derivatives. The results obtained from the CoMFA and CoMSIA study delineate the substituents on the trimethoprim analogues responsible for the enhanced potency and also provide valuable directions for the design of new trimethoprim analogues with improved affinity.
已经对大肠杆菌二氢叶酸还原酶抑制剂 2,4-二氨基-5-（取代苄基）嘧啶衍生物进行了三维定量构效关系（3D-QSAR）研究，以了解负责提高效力的结构特征。为了构建高度可预测的 3D-QSAR 模型，使用了比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法。预测模型显示出统计学上显著的交叉验证和非交叉验证相关系数 r2 CV 和 r2 nCV。使用结构多样化的测试集化合物对最终的 3D-QSAR 模型进行了验证。从 CoMFA 和 CoMSIA 方法生成的等高线图分析表明，在 R2 取代的第一和第二位取代电负性基团以及第三位取代的正电性基团显著增加了衍生物的效力。来自 CoMFA 和 CoMSIA 研究的结果描绘了三嗪类似物上的取代基，这些取代基负责增强效力，并且还为设计具有改善亲和力的新三嗪类似物提供了有价值的方向。
