【摘要】 细胞周期蛋白依赖性激酶(Cyclin-dependentKinases,CDKs)是细胞周期调控的重要因子,也是治疗癌症的一类重要的药物靶标.靛玉红是传统中药当归龙荟丸中治疗慢性疾病的有效成分,靛玉红及其衍生物5-磺酸基-靛玉红对CDKs具有有效的抑制作用.以获得晶体结构的CDK2与5-磺酸根-靛玉红的复合物为模板,通过同源模建和分子对接的方法构建出的CDK4与靛玉红及其衍生物的结合模式.结合CDK4与两种抑制剂的复合物结构,解释了靛玉红和衍生物5-磺酸基-靛玉红之间抑制活性的差别,同时也分析了5-磺酸基-靛玉红对CDK2和CDK4不同选择性的原因.所建CDK4结构为进一步进行基于结构的抗癌药物设计提供了合理的模型.更多还原

【Abstract】 Indirubin and its analogue, indirubin-5-sulphonic acid, have shown potent ability to inhibit cyclin-dependent-kinases (CDKs). Using the crystal structure of CDK2 complexed with indirubin-5- sulphonate as the template, models of CDK4 complexed with indirubin and its analogue were built by ho- mology modeling and molecular docking. The structure comparisons of CDK4 with indirubin and its ana- logue could explain different inhibition ability. Moreover, the different activity of indirubin-5-sulphonic acid complexed with CDK2 and CDK4 was also illustrated. The model structure provided the basis for designing more potent anticancer drug.更多还原