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

作者：Sun Li-Qian; Meng Li-Qiang; Yan Chao-Qun; Cui Dong-Xiao; Miao Jun-Qiu; Chen Jing-Run; Liang Tai-Gang^*; Li Qing-Shan^*

来源：Chinese Journal of Structural Chemistry, 2018, 37(4): 517-530.

DOI：10.14102/j.cnki.0254-5861.2011-1766

• 3D-QSAR
• CoMFA
• CoMSIA
• TFG-beta
• ALK5 inhibitor

The transforming growth factor-beta(TGF-beta) plays a crucial role in the beginning and progression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-beta 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 (3D-QSAR) including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to analyze the structural requirements based on a dataset of 123 4-([l,2,4]Triazolo[l,5-alpha]pyridine-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole analogues which acted as ALK5 inhibitors. The obtained CoMFA model (q(2) = 0.652, r(2)= 0.876, r(pred)(2) = 0.845) and CoMSIA model (q(2) = 0.648, r(2)= 0.884, r(Pred)(2)= 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 CoMFA and CoMSIA models. The results will be helpful to guide drug design strategies aimed at obtaining potent and selective ALK5 inhibitors.

• 出版日期2018-4-13
• 单位山西医科大学