Thermodynamic inhibition profile of a cyclopentyl and a cyclohexyl derivative towards thrombin: The same but for different reasons
Thermodynamic inhibition profile of a cyclopentyl and a cyclohexyl derivative towards thrombin: The same but for different reasons
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DOI：
10.1002/anie.200701169
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Klebe, Gerhard
中科院分区：
文献类型：
--
作者：
Gerlach, Christof;Smolinski, Michael;Klebe, Gerhard
在药物开发项目的过程中，通过系统地改变给定核心骨架上的官能团或侧链来优化预期的先导结构。如果有的话，参考目标蛋白的晶体结构来指导选择合适的取代基。药物化学家遵循一些为内在官能团贡献收集的基本规则，这些规则允许人们估计一旦连接或修饰特定官能团，结合亲和力预计会提高多少。[1-3]例如，根据吉布斯结合自由能，分配给亚甲基的基团贡献估计约为 3-4 kJ molÀ1。[1, 2]因此，在同属系列中，假设附加一个 如果受体能够适应这种取代，亚甲基将增加这个量的结合亲和力。每个添加的亚甲基的疏水结合增量增加的先决条件是同属系列内配体的类似结合行为。为了探讨这一概念，我们研究了同源凝血酶抑制剂对（1a 和 1b，方案 1），它们仅在设计用于结合 S3/S4 特异性口袋的环烷基取代基中的一个 CH2 单元不同。在我们设计这两种化合物时，我们以已知的美拉加群 (melagatran) 结合模式为指导 (2)，该模式很好地将环己基部分放入疏水性 S3/S4 口袋中。 [4]因此，我们选择了一个环己基部分和较小的环戊基部分来结合在 S3/S4 口袋中。1a 和 1b 的合成已在其他地方描述过。 [5]它们与凝血酶的结合常数通过动力学光度测定法测定。[6]令人惊讶的是，这两种抑制剂实际上具有相同的结合亲和力，而不是预期的 3–4-kJmolÀ1 结合亲和力增加
In the course of a drug development project prospective lead structures are optimized by systematically changing functional groups or side chains on a given core skeleton. If available, the crystal structure of the target protein is consulted to guide the selection of appropriate substituents. Medicinal chemists follow some basic rules collected for intrinsic functional group contributions that allow one to estimate by how much the binding affinity is expected to improve once a particular functional group is attached or modified.[1–3] For example, the group contribution assigned to a methylene group is estimated to about 3–4 kJ molÀ1 in terms of the Gibbs free energy of binding.[1, 2] Thus, within a congeneric series it is assumed that an additional methylene group will increase binding affinity by this amount if this substitution can be accommodated by the receptor. A prerequisite for the incremental increase in hydrophobic binding per added methylene group is the analogous binding behavior of ligands within a congeneric series. To probe this concept we studied the homologous pair of thrombin inhibitors (1a and 1b, Scheme 1) which differ only by one CH2 unit in the cycloalkyl substituent designed to bind in the S3/S4 specificity pocket. In our design of these two compounds, we were guided by the known binding mode of melagatran (2), which nicely places a cyclohexyl moiety into the hydrophobic S3/S4 pocket.[4] Consequently, we selected a cyclohexyl moiety and the smaller cyclopentyl moiety for binding in the S3/S4 pocket.The synthesis of 1a and 1b has been described elsewhere.[5] Their binding constants for thrombin were determined by a kinetic photometric assay.[6] Surprisingly, the two inhibitors had virtually the same binding affinity rather than the expected 3–4-kJmolÀ1 increase in binding affinity for