Ligand Specificity in Fragment-Based Drug Design
Ligand Specificity in Fragment-Based Drug Design
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DOI：
10.1021/jm100496j
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发表时间：
2010-07-22
影响因子：
7.3
通讯作者：
Krimm, Isabelle
中科院分区：
文献类型：
--
作者：
Barelier, Sarah;Pons, Julien;Krimm, Isabelle
基于片段的药物设计包括识别与目标大分子弱结合的低分子量化合物，然后对其进行修饰或连接以产生有效的抑制剂。文献中很少讨论这些低复杂性和低亲和力分子的特异性。为了解决这个问题，使用核磁共振波谱研究了 150 个片段与 5 种蛋白质的相互作用：Bcl-2 家族的三种蛋白质（Bcl-x(L)、Bcl-w 和 Mcl-1）、人过氧化还原蛋白 5（其配体报道很少）和人血清白蛋白（已知与大量配体结合）。我们的结果表明，这些片段是相当通用的结合物，能够识别非常不同的目标中的结合热点。尽管观察到与蛋白质成药性相关的命中率不同，但两种支架似乎是所有蛋白质的首选结合物。在同源蛋白质或不相关的药物性差的蛋白质之间观察到低特异性，而高度药物性靶标可以实现更高的特异性。
Fragment-based drug design consists of identifying low-molecular weight compounds that weakly bind to a target macromolecule and will then be modified or linked to yield potent inhibitors. The specificity of these low-complexity and low-affinity molecules has rarely been discussed in the literature. To address this question, NMR spectroscopy was used to investigate the interactions of 150 fragments with five proteins: three proteins from the Bcl-2 family (Bcl-x(L), Bcl-w, and Mcl-1), human peroxiredoxin 5, for which very few ligands have been reported, and human serum albumin, which is known to bind a large number of ligands. Our results show that the fragments are rather versatile binders and able to identify binding hot spots in very different targets. Despite the different hit rates observed related to the druggability of the proteins, two scaffolds appear as preferred binders for all proteins. Low specificity was observed between homologous proteins or unrelated poorly druggable proteins, while higher specificity could be achieved with highly druggable targets.