Laboratoire des Sciences Analytiques, UMR CNRS 5180, Universite de Lyon, Universite Claude Bernard, Lyon 1, Bat. ESCPE Lyon, Domaine Scientifique de la Doua, 69100 Villeurbanne, France.
J Med Chem. 2010 Jul 22;53(14):5256-66. doi: 10.1021/jm100496j.
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.
基于片段的药物设计包括确定与靶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，以生成有效的抑制剂。这些低复杂度和低亲和力分子的特异性在文献中很少被讨论。为了解决这个问题，我们使用 NMR 光谱学研究了 150 个片段与 5 种蛋白质之间的相互作用：3 种 Bcl-2 家族蛋白（Bcl-x(L)、Bcl-w 和 Mcl-1）、人过氧化物酶 5，很少有报道其配体，以及人血清白蛋白，已知其能结合大量配体。我们的结果表明，这些片段是相当通用的结合物，能够识别非常不同靶标中的结合热点。尽管与蛋白质的可成药性相关的命中率不同，但有两种骨架似乎是所有蛋白质的首选结合物。在同源蛋白或不相关的、难以成药的蛋白质之间观察到低特异性，而在高度可成药的靶标上可以实现更高的特异性。
