Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.
Nat Chem. 2011 Nov 20;4(2):99-104. doi: 10.1038/nchem.1200.
The discovery of new compounds for the pharmacological manipulation of protein function often embraces the screening of compound collections, and it is widely recognized that natural products offer beneficial characteristics as protein ligands. Much effort has therefore been focused on 'natural product-like' libraries, yet the synthesis and screening of such libraries is often limited by one or more of the following: modest library sizes and structural diversity, conformational heterogeneity and the costs associated with the substantial infrastructure of modern high-throughput screening centres. Here, we describe the design and execution of an approach to this broad problem by merging principles associated with biologically inspired oligomerization and the structure of polyketide-derived natural products. A novel class of chiral and conformationally constrained oligomers is described (termed 'chiral oligomers of pentenoic amides', COPA), which offers compatibility with split-and-pool methods and can be screened en masse in a batch mode. We demonstrate that a COPA library containing 160,000 compounds is a useful source of novel protein ligands by identifying a non-covalent synthetic ligand to the DNA-binding domain of the p53 transcription factor.
新化合物的发现对于蛋白质功能的药理学操纵常常涉及化合物库的筛选，人们普遍认为天然产物作为蛋白质配体具有有益的特性。因此，人们已经投入了大量的精力来研究“类似天然产物”的文库，然而，这类文库的合成和筛选往往受到以下一个或多个因素的限制：文库的规模和结构多样性较小、构象异质性以及与现代高通量筛选中心的大量基础设施相关的成本。在这里，我们描述了一种通过将与生物启发的聚合以及聚酮衍生天然产物结构相关的原理相结合来解决这一广泛问题的方法的设计和执行。我们描述了一类新型的手性和构象受限的低聚物（称为“戊烯酰胺的手性低聚物”，COPA），它与分裂和池法兼容，可以批量进行筛选。我们通过鉴定 p53 转录因子 DNA 结合结构域的非共价合成配体，证明了包含 160,000 个化合物的 COPA 文库是一种新型蛋白质配体的有用来源。
