Institut des Sciences Analytiques, UMR CNRS 5280, Université de Lyon, Université Claude Bernard Lyon 1, Bât. CPE Lyon, Domaine scientifique de la Doua, F-69622 Villeurbanne, France.
J Med Chem. 2012 Feb 9;55(3):1287-95. doi: 10.1021/jm201439b. Epub 2012 Jan 24.
Fragment-based drug discovery has become a powerful method for the generation of drug leads against therapeutic targets. Beyond the identification of novel and effective starting points for drug design, fragments have emerged as reliable tools for assessing protein druggability and identifying protein hot spots. Here, we have examined fragments resulting from the deconstruction of known inhibitors from the glycogen phosphorylase enzyme, a therapeutic target against type 2 diabetes, with two motivations. First, we have analyzed the fragment binding to the multiple binding sites of the glycogen phosphorylase, and then we have investigated the use of fragments to study allosteric enzymes. The work we report illustrates the power of fragmentlike ligands not only for probing the various binding pockets of proteins, but also for uncovering cooperativity between these various binding sites.
基于片段的药物发现已经成为针对治疗靶点生成药物先导物的一种强大方法。除了鉴定新颖有效的药物设计起点外，片段还已成为评估蛋白质可成药性和鉴定蛋白质热点的可靠工具。在这里，我们研究了从糖原磷酸化酶（一种针对 2 型糖尿病的治疗靶点）的已知抑制剂中解构得到的片段，这有两个动机。首先，我们分析了片段与糖原磷酸化酶的多个结合位点的结合情况，然后我们研究了使用片段来研究别构酶。我们报告的工作说明了片段样配体的强大功能，不仅可以探测蛋白质的各种结合口袋，还可以揭示这些各种结合位点之间的协同作用。
