Spanning binding sites on allosteric proteins with polymer-linked ligand dimers
Spanning binding sites on allosteric proteins with polymer-linked ligand dimers
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DOI：
10.1038/27227
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发表时间：
1998-10-15
期刊：
影响因子：
64.8
通讯作者：
Karpen, JW
中科院分区：
文献类型：
--
作者：
Kramer, RH;Karpen, JW
药物设计的一种方法是确定靶蛋白上结合位点的结构，为配体的构建提供模板。另外，化学基团的随机组合可以用来产生不同的分子，以便在寻找有效化合物时进行筛选。在这里，我们报告了一种为具有多个结合位点的蛋白质开发有效配体的策略，它结合了两种方法的元素：聚合物连接的配体二聚体：其中两个配体由可变长度的聚合物链连接。我们发现含有两个环GMP片段的聚合物连接配体二聚体在激活环核苷酸门控通道和cgmp依赖性蛋白激酶方面的效力是环GMP的一千倍。每种靶蛋白对具有不同平均聚合物长度的聚合物连接配体二聚体反应最佳，即使它们的环核苷酸结合位点是保守的。聚合物连接配体二聚体的调谐表明每种蛋白质具有独特的结合位点间距，并提供了这些位点之间距离的估计。由于最佳配体是根据经验选择的，聚合物连接配体二聚体策略可以在不需要先前有关目标蛋白的结构信息的情况下识别有效和选择性的药物。
One approach to drug design involves determination of the structure of binding sites on target proteins to provide templates for ligand construction. Alternatively, random combinations of chemical groups can be used to generate diverse molecules for screening in the search for effective compounds'. Here we report a strategy for developing potent ligands for proteins with multiple binding sites, which combines elements of both approaches: 'polymer-linked ligand dimers: in which two ligands are joined by a polymer chain of variable length. We find that polymer-linked ligand dimers containing two cyclic GMP moieties are up to a thousand times more potent than cyclic GMP in activating cyclic-nucleotide-gated channels and cGMP-dependent protein kinase. Each target protein responds optimally to a polymer-linked ligand dimer with a different average polymer length, even though their cyclic-nucleotide-binding sites are conserved. The tuning of polymer-linked ligand dimers indicates that each protein has a unique spacing of binding sites and provides an estimate of the distance between these sires. As optimal ligands are selected empirically, the: polymer-linked Ligand dimer strategy enables potent and selective agents to be identified without requiring previous structural information about the target proteins.