Mtb_G5K同源建模及其与[3,2-c]喹啉对接研究

Homology modeling of Mtb_G5K and its docking mode with[3,2-c]quinolone

结核病一直困扰着人类的健康。谷氨酸5-激酶(G5K,Glutamate 5-Kinase)作为新型抗结核药物靶标,小分子活化剂与其结合后,激活生物合成途径,会产生过量的脯氨酸和活性氧,从而杀死结核分枝杆菌(Mtb)。本文基于结核分枝杆菌谷氨酸5-激酶(Mtb_G5K)的一级序列,采用同源模建的方法构建Mtb_G5K蛋白三维结构并对其优化,运用三种方法分别对模型的各个方面进行评估,从而得到合理的蛋白质三维模型;构建小分子并将其能量最小化获得药物分子的最低能量构象,用Autodock将小分子对接到Mtb_G5K的活性位点;分析探讨[3,2-c]喹啉类小分子结合模式,观察蛋白与小分子之间的相互作用并预测具有稳定结合的高活性药物,从而推断出喹啉环的取代基采用相对分子质量较大的官能团能够增强药物小分子的酶催化活性。本研究结果对将来抗结核小分子的研发设计提供了新的思路。

Tuberculosis has been making human health in trouble.Glutamate 5-kinase(G5K)is a new target of anti-tuberculosis drugs.When G5K combined with small molecules,it activates the biosynthetic pathway and produces excessive proline and reactive oxygen,thus killing Mycobacterium tuberculosis(Mtb,Mycobacterium tuberculosis).In our research,based on the primary sequence Mtb_G5K,homology modeling method was used to construct and optimize the three-dimensional(3D)structure of the Mtb_G5K,and all aspects of the model were evaluated by three methods to obtain a reasonable 3D model.To obtain the minimum energy structure of drug molecules,Autodock was used to do docking between small molecules and Mtb_G5K,and the binding mode was analyzed and discussed.The interaction between small molecules of[3,2-c]quinoline and proteins was used as a reference to predict the direction of modification of high-activity drugs with stable binding mode.It was inferred that the substituents of quinoline ring can enhance the enzymatic catalytic activity of small drug molecules by using relatively large functional groups.The results of this study may provide a new idea for the development and design new small molecules of anti-tuberculosis in the future.