COMBINATORIAL TARGET-GUIDED LIGAND ASSEMBLY

小分子文库的组合生成方法 再加上高通量筛选，已经成为 受体和酶的小分子配体的鉴定。这个 已识别的配体是药理学研究的有力工具， 对药物开发至关重要。组合方法是最多的 当信息被用来设计分子库时，成功 做好准备和测试。在这些努力中，库的设计使用 了解生物靶标的机制或结构，或通过建立 先前已确定结合的先导化合物(S)上的文库 对生物目标的影响。不幸的是，对于许多生物目标来说，结构性 或者机械性的信息不可用或没有提供足够的信息 洞察力，以实现高效的库设计。此外，对于许多目标来说， 尚未确定先导化合物或用于结合的新基序是 想要。毫不奇怪，在这种情况下，准备和 对图书馆的筛查就不那么成功了，因为我们可以准备和 只测试大于1060的小的无穷小的一部分 理论上可以准备好的分子。在此，我们建议 开发一种有效的新方法来快速识别小分子 生物靶标的配体称为组合靶标导向配体 集合。该方法包括四个连续、简单的步骤，并且 不依赖于先导化合物，也不需要了解其机理或 生物目标的结构。(1)一组潜在的结合元件是 制备的，其中SET的每个分子必须溶于水溶液 在高浓度下，必须包含一个共同的化学连接基团。 (2)在高浓度下筛选该组潜在结合元素以 识别所有与生物体相互作用甚至很弱的结合元素 目标。(3)构建了连锁结合元件组合文库 由此使用共同的化学键连接结合元件 通过一组灵活的链接器进行分组。(4)组合函数库 筛选连接的结合元件以识别最紧密的结合配体。

Combinatorial methods for generating small molecule libraries coupled with high throughput screening have become core technologies for the identification of small molecule ligands to receptors and enzymes. The identified ligands serve as powerful tools for pharmacological studies and are essential to drug development. Combinatorial approaches have been most successful when information has been used to design the library of molecules to be prepared and tested. In these efforts, libraries are designed using knowledge of the mechanism or structure of the biological target, or by basing the library upon lead compound(s) that have previously been identified to bind to the biological target. Unfortunately, for many biological targets structural or mechanistic information is not available or does not provide sufficient insight to enable productive library design. Additionally, for many targets, lead compounds have not yet been identified or novel motifs for binding are desired. Not surprisingly, under these circumstances the preparation and screening of libraries has been much less successful, since we can prepare and test only an infinitesimally small fraction of the greater than 1060 small molecules that could theoretically be prepared. Herein, we propose the development of a powerful new approach to rapidly identify small molecule ligands to biological targets called combinatorial target-guided ligand assembly. The method involves four sequential, straightforward steps and does not rely on lead compounds nor does it require knowledge of the mechanism or structure of the biological target. (1) A set of potential binding elements is prepared wherein each molecule of the set must be soluble in aqueous solution at high concentrations and must incorporate a common chemical linkage group. (2) The set of potential binding elements is screened at high concentrations to identify all binding elements that interact even weakly with the biological target. (3) A combinatorial library of linked binding elements is prepared whereby the binding elements are connected using the common chemical linkage groups through a set of flexible linkers. (4) The combinatorial library of linked binding elements is screened to identify the tightest binding ligands.