Thermodynamical properties of protein kinase with adenine inhibitors  

作　　者：WU LingZhi HU Dong TANG LiHua HU XiaoFei QIN Meng 

机构地区：[1]School of Geography and Biological Information,Nanjing University of Posts and Telecommunications [2]State Key Laboratory of Bioelectronics,School of Biological Science and Medical Engineering,Southeast University [3]National Laboratory of Solid State Microstructure,Department of Physics,Nanjing University

出　　处：《Chinese Science Bulletin》2013年第1期68-73,共6页

基　　金：supported by the National Natural Science Foundation of China (61101056);the Open Project of State Key Laboratory of Bioelectronics of Southeast University (2011E14);the China Postdoctoral Science Foundation (20110491339);the Scientific Research Foundation of Nanjing University of Posts and Telecommunications (NY210082)

摘　　要：The protein-based molecular recognition of the adenine ring is essential to understand protein function and drug design as well.In this paper,a variety of the adenine-based inhibitors with modified groups of amino groups,nitrogen and oxygen atoms in the aromatic ring are designed,and the binding capability of these adenosine analogues with an aminoglycoside antibiotic kinase [APH(3')-IIIa] are investigated with activity assays and isothermal titration calorimetry(ITC) experiments.1-aminoisoquinoline is one of the weakest substrates bound to APH(3')-IIIa with the lowest affinity(high ki and high kd) and the smallest negative value of free energy change(G) among the inhibitors tested.The binding process of adenine and 5-nitroisoquinoline to APH(3')-IIIa is an enthalpy-driven event with unfavorable entropy,which is consistent with the energy change induced by the binding of ATP to the enzyme.However,the reverse is true for 1-aminoisoquinoline,3-amino-5-nitrobenzisothiazole,5-aminoisoquinoline binding to the enzyme because the entropy is more favorable and the enthalpy makes a lower contribution to the binding process.These results suggest that small changes of the adenine ring can lead to significant influence on the ability of these analogues to occupy the adenine-binding region of the enzyme,which can be the potential inhibitors as drug candidates against the bacterial resistance.The protein-based molecular recognition of the adenine ring is essential to understand protein function and drug design as well. In this paper, a variety of the adenine-based inhibitors with modified groups of amino groups, nitrogen and oxygen atoms in the aromatic ring are designed, and the binding capability of these adenosine analogues with an aminoglycoside antibiotic kinase [APH（3＇）-IIIa] are investigated with activity assays and isothermal titration calorimetry （ITC） experiments. 1-aminoisoquinoline is one of the weakest substrates bound to APH（3＇）-IIIa with the lowest affinity （high ki and high ka） and the smallest negative value of free energy change （AG） among the inhibitors tested. The binding process of adenine and 5-nitroisoquinoline to APH（3＇）-IIIa is an enthalpy-driven event with unfavorable entropy, which is consistent with the energy change induced by the binding of ATP to the enzyme. However, the reverse is true for 1-aminoisoquinoline, 3-amino-5-nitrobenzisothiazole, 5-aminoisoquinoline binding to the enzyme because the entropy is more favorable and the enthalpy makes a lower contribution to the binding process. These results suggest that small changes of the adenine ring can lead to significant influence on the ability of these analogues to occupy the adenine-binding region of the enzyme, which can be the potential inhibitors as drug candidates against the bacterial resistance.

关 键 词：蛋白激酶 腺嘌呤 抑制剂 热力学性质 氨基糖苷类抗生素 药物设计 结合能力 异喹啉 

分 类 号：Q55[生物学—生物化学]