3D-QSAR Studies on 4-([1,2,4]Triazolo[1,5-α]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole Analogues as Potent Inhibitors of Transforming Growth Factor-β Type Ⅰ Receptor Kinase

The transforming growth factor-β(TGF-β) plays a crucial role in the beginning and progression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-β type I receptor kinase(activin receptor-like kinase 5, ALK5) inhibitors might have potential activity for the treatment of relevant diseases. In this paper, the three-dimensional quantitative structure-activity relationship(3 D-QSAR) including comparative molecular field analysis(Co MFA) and comparative molecular similarity indices analysis(Co MSIA) were used to analyze the structural requirements based on a dataset of 123 4-([1,2,4]Triazolo[1,5-α]pyridine-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole analogues which acted as ALK5 inhibitors. The obtained Co MFA model(q~2 = 0.652, r~2 = 0.876, r~2 pred = 0.845) and Co MSIA model(q~2 = 0.648, r~2 = 0.884, r~2 pred = 0.853) were robust and satisfactory. The predictive ability of the derived models was validated using a test set of 28 compounds. Additionally, potentially important structural features required to enhance activity were also elucidated by the contour maps derived from Co MFA and Co MSIA models. The results will be helpful to guide drug design strategies aimed at obtaining potent and selective ALK5 inhibitors.     

1,3-二取代咪唑类离子液体熔点预测

以16种咪唑类四氟硼酸盐和22种咪唑类六氟磷酸盐为研究对象, 采用QSAR(quantitative structure-activity relationship)方法和遗传算法对其熔点与结构的定量构效关系进行了研究, 以实现对两类咪唑类离子液体熔点的预测. 建立的咪唑类四氟硼酸盐三参数模型相关系数R2为0.89, 咪唑类六氟磷酸盐四参数模型相关系数R2为0.85; 使用留一法对两模型进行内部验证的相关系数R2分别为0.82和0.77, 两预测模型具有真实有效性; 使用测试集对两模型进行外部验证, 所得两模型的平均预测绝对误差分别为11.43和7.78 K, 优于文献报道水平, 可得出结论, 两模型均具有较好的熔点预测能力.