咪唑类ALK5抑制剂的3D-QSAR及分子对接研究  

3D-QSAR and docking studies on imidazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors

作　　者：项瑶 赵钟祥[1] 陈静波[2] 马玉卓 刘鹰翔[1] 熊迪[3] 

机构地区：[1]广州中医药大学中药学院,广东广州510006 [2]云南大学教育部自然资源药物化学重点实验室,云南昆明650091 [3]广东药科大学药学院,广东广州510006

出　　处：《云南大学学报（自然科学版）》2017年第4期633-642,共10页Journal of Yunnan University(Natural Sciences Edition)

基　　金：国家自然科学基金(81270054);广东省高等学校优秀青年教师培养计划(Yq2013045)

摘　　要：TGF-β信号的异常与肿瘤、肾脏和肝脏纤维化等疾病密切相关,其传导通路中的TypeⅠ受体(ALK5)是针对相关疾病的重要作用靶标蛋白.以候选药物EW7197作为模板分子,构建比较分子场分析(CoMFA)模型和比较分子相似性指数分析(CoMSIA)模型,对61个咪唑类ALK5抑制剂的结构与其活性的相互关系进行分析,得到2个最佳模型的交叉验证系数q^2分别为0.716、0.704,相关系数r^2分别为0.905、0.976;综合2个模型的势能图发现,氢键受体场和疏水场对抑制剂的活性影响最大.应用分子对接探讨了蛋白靶标和抑制剂之间的结合模式以及重要的相互作用.综合3D-QSAR分析和分子对接结果,希望为设计新型高效、低毒的ALK5抑制剂提供科学依据.ALK5 inhibitors, which can inhibit TGF-β signaling pathway, play a vital role in medicine for treatment of many diseases, such as cancer, renal fibrosis and liver fibrosis.Herein, TGF-β signaling inhibitors of 61 imidazole-based derivatives compounds for ALK5 were analyzed using common skeleton-based 3D-QSAR.We selected EW7197 as a template to generate common substructure-based alignmentsand further built both CoMFA and CoMSIA models.Through the values of r^2 and q^2 obtained,we may judge the merits of these models.The results indicate that the optimal CoMFA model has q^2= 0.716 and r^2= 0.905, the optimal CoMSIAmodel has q^2= 0.704 and r^2 = 0.976.The outcomes of contour maps show that the hydrogen bond acceptor and hydrophobic features play key roles in models. Furthermore, the docking studies revealed important interactions between compounds and amino acids,and the obtained binding mode was in good agreement with the 3D-QSAR results.Based on our analysis and affirmation of docking simulations, we may lay a reliable theoretical foundation for designing new potential ALK5 inhibitors with higher activity and affinity.

关 键 词：TGF-βⅠ型受体激酶 ALK5抑制剂 咪唑类衍生物 比较分子场分析 比较分子相似性指数分析 分子对接 

分 类 号：TQ450.11[化学工程—农药化工] O625.63[理学—有机化学]