Finding a better path to drug selectivity.
Finding a better path to drug selectivity.
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DOI：
10.1016/j.drudis.2011.07.010
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发表时间：
2011-11
影响因子：
7.4
通讯作者：
Freire, Ernesto
中科院分区：
文献类型：
--
作者：
Kawasaki, Yuko;Freire, Ernesto
极高的亲和力和选择性是药物分子最受欢迎的两个特性。选择性很难实现，特别是对于属于结构和功能相关蛋白质大家族的靶标。在先导化合物优化过程中，本质上有两种方法可以提高选择性[AU1]：对先导化合物进行化学修饰，将其对靶标的亲和力提高到比对脱靶分子的亲和力更高的程度；以及降低先导化合物对脱靶分子的亲和力的化学修饰。当两种机制可以协同结合时，可以实现最大选择性。正如我们在这里讨论的，对单一功能不同的几种蛋白酶抑制剂的分析表明，非极性功能优先遵循第一种机制，而极性功能遵循第二种机制，并且这些特征印在其热力学特征中。
Extremely high affinity and selectivity are two of the most sought-after properties of drug molecules. Selectivity has been difficult to achieve, especially for targets that belong to large families of structurally and functionally related proteins. There are essentially two ways [AU1] by which selectivity can be improved during lead optimization: a chemical modification of the lead compound that improves the affinity towards the target to a higher extent than to off-target molecules; and a chemical modification that lowers the affinity of the lead compound towards off-target molecules. Maximal selectivity is achieved when both mechanisms can be combined synergistically. As we discuss here, analysis of several protease inhibitors that vary in a single functionality indicates that nonpolar functionalities preferentially follow the first mechanism, whereas polar functionalities follow the second, and that those features are imprinted in their thermodynamic signatures.
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影响因子：
2.9
作者：
Schon, Arne;Madani, Navid;Freire, Ernesto
通讯作者：
Freire, Ernesto
影响因子：
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Freire, Ernesto
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作者：
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