Dynamic Combinatorial Chemistry - In Drug Discovery, Bioorganic Chemistry, and Materials Science
Dynamic Combinatorial Chemistry - In Drug Discovery, Bioorganic Chemistry, and Materials Science
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动态组合化学 - 在药物发现、生物有机化学和材料科学中
DOI：
10.1002/9780470551554.ch2
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Greaney M
中科院分区：
文献类型：
--
作者：
Greaney M
使用蛋白质来控制动态组合文库（DCL）的进化一直是该领域发展的核心，因为该领域的第一篇出版物出现在20世纪90年代末[1]。蛋白质导向的DCL概念很简单：化合物的DCL被设计成可以在蛋白质存在下平衡。由于文库群体分布受热力学控制，因此通过选择性结合蛋白质稳定一个成员预计会以其他（非结合）物质为代价扩增该物质，产生可以通过分析DCL群体分布鉴定的命中结构[2]。因此，蛋白质导向的动态组合化学（DCC）提供了一种研究、发现和排序新型蛋白质结合配体的方法，这些配体是药物化学的基础概念[3-6]。在这些方面，DCC过程弥合了候选药物的化学合成与其生物结合测定之间的差距，将两个操作啮合成单个过程，由此生物靶标的结构指导其自身最佳抑制剂的原位组装。蛋白质靶标是DCC中具有挑战性的模板。它们对pH值、温度和化学试剂的敏感性显著限制了合成化学，
The use of proteins to control the evolution of dynamic combinatorial libraries (DCLs) has been central to the development of the field, since the first publications in the area appeared in the late 1990s [1]. The proteindirected DCL concept is a simple one: A DCL of compounds is designed such that it can equilibrate in the presence of a protein. Since the library population distribution is under thermodynamic control, stabilization of one member through selective binding to the protein is expected to amplify that species at the expense of other (nonbinding) species, generating hit structures that can be identified through analysis of the DCL population distribution [2]. Protein-directed dynamic combinatorial chemistry (DCC) thus provides a method for studying, discovering, and ranking novel protein-binding ligands, concepts fundamental to medicinal chemistry [3–6]. In these terms, the DCC process bridges the gap between chemical synthesis of drug candidates and their biological binding assay, meshing the two operations into a single process whereby the structure of the biological target directs the assembly of its own best inhibitor in situ. Protein targets are challenging templates to work with in DCC. Their sensitivity to pH, temperature, and chemical reagents places significant restraint on the synthetic chemistry that can be successfully used in