COMBINATORIAL TARGET-GUIDED LIGAND ASSEMBLY

组合靶标引导配体组装

• 批准号: 6262613
• 负责人: JONATHAN A ELLMAN
• 金额: $ 22.91万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6262613
• 关键词: X ray crystallography; benzodiazepine receptor; benzodiazepines; biotechnology; chemical binding; chemical structure function; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; enzyme linked immunosorbent assay; high throughput technology; ligands; mass spectrometry; technology /technique development

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.

用于产生小分子文库的组合方法 与高通量筛选相结合，已成为 识别受体和酶的小分子配体。的 已鉴定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 当信息被用于设计分子库时， 准备和测试。在这些努力中，库是使用 生物靶标的机制或结构的知识，或者通过基于 该文库基于先前已被鉴定为结合的先导化合物 生物目标。不幸的是，对于许多生物靶标结构， 或机械信息不可用或未提供足够的 洞察力，以实现高效的库设计。此外，对于许多目标， 先导化合物尚未被鉴定，或者用于结合的新基序， 需要的话毫不奇怪，在这种情况下， 筛选文库的成功率要低得多，因为我们可以制备和 只测试一个无穷小的分数大于1060小 理论上可以制备的分子。在此，我们建议 开发一种快速识别小分子的强大新方法 称为组合靶向配体 组装件.该方法包括四个连续的、简单的步骤， 不依赖于先导化合物，也不需要了解其机制， 生物目标的结构。(1)一组潜在的绑定元素是 其中组的每个分子必须可溶于水溶液 在高浓度下，并且必须包含共同的化学连接基团。 (2)在高浓度下筛选潜在结合元件组， 识别所有与生物分子相互作用甚至很弱的结合元件， 目标(3)制备连接的结合元件的组合文库， 其中结合元件使用共同的化学键连接 通过一组灵活的连接基团。(4)的组合文库 筛选连接的结合元件以鉴定最紧密的结合配体。