Briesewitz R, Ray G T, Wandless T J, Crabtree G R
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1953-8. doi: 10.1073/pnas.96.5.1953.
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.
描述了一种用于改善小分子配体与蛋白质靶标结合特性的通用策略。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化学连接来创建双功能分子。当感兴趣的配体由第二种蛋白质呈现给靶蛋白时，配体结合位点之外的额外蛋白质 - 蛋白质相互作用可用于增加或降低结合事件的亲和力。我们已将此方法应用于一个难以处理的靶标——SH2结构域，并证明其比天然肽的亲和力提高了3倍。这种方法提供了一种调节生物活性化合物效力和特异性的途径。
