COMBINATORIAL APPROACH TO ARTIFICIAL RECEPTOR DESIGN

组合策略的力量对于产生大的 分子种群在生物学上早已被认识到。一直以来 估计5x10-7形成B细胞的新抗体是在 人体每天都会产生一种独特的抗体分子。如此巨大 品种提供了大范围的结合区域，可供选择 它们与免疫系统中的靶抗原具有互补性。在……里面 近年来，越来越多的人试图重现 中、大、小图书馆产生的多样性 分子。这些组合方法已经被引导到形成 寡聚体或小分子文库，其设计用于与 靶(通常是生物的)受体。这项提案的主要重点是 是以开发合成受体文库为基础的吗 提出了一种新的金属离子和分子传感器设计方法。卓有成效的 受体需要在井中存在多个结合基团- 限定的空间排列并指向中心结合裂隙 或者空洞。这只能通过收敛的方法来实现，该方法允许 在将它们组装在一起之前要预先形成不同的结合区 以生成最终的识别站点。 这项提议代表了一项旨在发展 人工智能文库设计的组合方法 分子受体。其核心概念是一种模板金属 支架既可以作为结构多样性的一步来源发挥作用 并作为底物结合的内部光谱探针。因此，两者 解决了组合化学中的关键问题；一种简便的 到功能库的兼容路线和内部筛选设备 用于确定强而有效的结合配体。强者的力量 组合的方法是它允许生成一个大型的库 合成的分子或金属离子受体，然后可以筛选 所需的选择性。为了实现这些目标，我们将准备一系列 具有不同结合区域的联吡啶配体的官能化 然后会围绕一个过渡金属中心自组装。内部 然后将使用光谱探针来筛选受体文库 对一系列具有生物学意义的物质具有很强的选择性结合 底物。我们预计受体文库策略可以是 扩展到形成金属模板的电离团，改变了它们的 与目标金属离子结合时的比色或荧光性质。 我们还将制备一系列功能化的联吡啶衍生物 金属，将形成一个金属模板识别网站与三个 潜在底物结合区。

The power of combinatorial strategies for the generation of large populations of molecules has long been recognized in biology. It has been estimated that 5xlO-7 new antibody forming B cells are produced in the body every day, each producing a unique antibody molecule. This enormous variety provides a large range of binding regions that can be selected for their given complementarity for a target antigen in the immune system. In recent years there have been increasing attempts to reproduce the power of diversity in the generation of medium and large libraries of small molecules. These combinatorial methods have been directed to the formation either of oligomeric or of small molecule libraries designed to bind to a target (usually biological) receptor. The primary focus of this proposal is the development of libraries of synthetic receptors as the foundation of a novel approach to metal ion and molecule sensor design. An effective receptor requires the presence of multiple binding groups in a well- defined spacial arrangement and directed towards a central binding cleft or cavity. This can only be achieved by a convergent approach which allows different binding regions to be pre-formed before assembling them together to generate the final recognition site. This proposal represents a major new program aimed at the development of a combinatorial approach to the design of libraries of artificial molecular receptors. The central concept is that a templating metal scaffold can function both as a one step source of structural diversity and as an internal spectroscopic probe of substrate binding. Thus, both key problems in combinatorial chemistry are solved; a facile and compatible route to functional libraries and an internal screening device for identifying strong and effective binding ligands. The strength of the combinatorial approach is that it allows the generation of a large library of synthetic molecule or metal ion receptors that can then be screened for the desired selectivity. To achieve these goals we will prepare a series of terpyridine ligands functionalized with different binding regions which will then self-assemble around a transition metal center. The internal spectroscopic probe will then be used to screen the receptor library for strong and selective binding to a range of biologically interesting substrates. We anticipate that the receptor library strategy can be extended to the formation metal templated ionophores that change their colorimetric or fluorescence properties on binding to target metal ions. We will also prepare a series of functionalized bipyridine derivatives metal that will form a metal templated recognition site with three potential substrate binding regions.