Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces
Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces
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DOI：
10.1073/pnas.96.5.1953
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发表时间：
1999-03-02
影响因子：
11.1
通讯作者：
Crabtree, GR
中科院分区：
文献类型：
--
作者：
Briesewitz, R;Ray, GT;Crabtree, GR
描述了改善小分子配体与蛋白质靶标的结合特性的一般策略。双功能分子是通过将感兴趣的配体与另一个与第二种蛋白质紧密结合的小分子进行化学连接而产生的。当目标配体被第二个蛋白质呈递给靶蛋白时，配体结合位点之外的额外蛋白质-蛋白质相互作用可以增加或减少结合事件的亲和力。我们已将这种方法应用于难以处理的靶标 SH2 结构域，并证明其比天然肽增强了 3 倍。这种方法提供了一种调节生物活性化合物的效力和特异性的方法。
A general strategy is described for improving the binding properties of small-molecule ligands to protein targets. A bifunctional molecule is created by chemically linking a ligand of interest to another small molecule that binds tightly to a second protein. When the ligand of interest is presented to the target protein by the second protein, additional protein-protein interactions outside of the ligand-binding sites serve either to increase or decrease the affinity of the binding event. We have applied this approach to an intractable target, the SH2 domain, and demonstrate a 3-fold enhancement over the natural peptide. This approach provides a way to modulate the potency and specificity of biologically active compounds.