Wolfenden R
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27514.
Pharmacol Ther. 1993 Nov;60(2):235-44. doi: 10.1016/0163-7258(93)90008-2.
An enzyme can enhance the rate of a reaction only to the extent that it binds the altered substrate in the transition state (S not equal to) more tightly than it binds the substrate in the ground state. Inhibitors that resemble S not equal to can be used to stop an enzyme from working, probe its mechanism of action and obtain exact structural information about intermediates in catalysis. In S not equal to analog inhibitors of adenosine and cytidine deaminases, a single hydroxyl group appears to make extremely large contributions to binding affinity. The magnitude of this contribution becomes even more striking when differences in free energy of solvation by water are taken into account. Other results, obtained by deleting individual binding determinants, indicate the operation of remarkable levels of cooperativity and suggest that if every group is in exactly the right position and is part of an inflexible structure, then a single substituent or H-bond can produce very large increases in binding affinity. Some implications for inhibitor design are considered.
一种酶只能在其与处于过渡态（S≠）的改变后的底物结合比与基态的底物结合更紧密的程度上提高反应速率。类似于S≠的抑制剂可用于阻止酶发挥作用、探究其作用机制并获取有关催化中间体的确切结构信息。在腺苷脱氨酶和胞苷脱氨酶的S≠类似物抑制剂中，单个羟基似乎对结合亲和力有极大贡献。当考虑到水溶剂化自由能的差异时，这种贡献的程度变得更加显著。通过删除单个结合决定因素获得的其他结果表明存在显著水平的协同作用，并表明如果每个基团都处于恰好正确的位置并且是刚性结构的一部分，那么单个取代基或氢键可以使结合亲和力大幅增加。文中考虑了对抑制剂设计的一些启示。
