Wang Yikai, Wach Jean-Yves, Sheehan Patrick, Zhong Cheng, Zhan Chenyang, Harris Richard, Almo Steven C, Bishop Joshua, Haggarty Stephen J, Ramek Alexander, Berry Kayla N, O'Herin Conor, Koehler Angela N, Hung Alvin W, Young Damian W
Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
ACS Med Chem Lett. 2016 Jul 14;7(9):852-6. doi: 10.1021/acsmedchemlett.6b00230. eCollection 2016 Sep 8.
Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound.
传统的基于片段的药物发现（FBDD）严重依赖于与靶点结合的命中物的结构分析。在此，我们提出一种基于多样化导向合成（DOS）的互补方法。基于DOS的片段库能够产生针对靶点糖原合成酶激酶3β（GSK3β）的初始命中化合物，允许系统合成相关片段类似物以探索片段水平的构效关系，并最终导向合成一种活性更强的化合物。
