COMBINATORIAL TARGET-GUIDED LIGAND ASSEMBLY

组合靶标引导配体组装

• 批准号: 6699046
• 负责人: JONATHAN A ELLMAN
• 金额: $ 20.63万
• 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/6699046
• 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.

生成小分子文库的组合方法 加上高通量筛选已成为核心技术 识别受体和酶的小分子配体。这 已鉴定的配体可作为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 当信息被用来设计分子库时就成功了 做好准备并进行测试。在这些努力中，库的设计使用 了解生物靶标的机制或结构，或通过基础 先前已确定可结合的先导化合物的文库 达到生物学目标。不幸的是，对于许多生物目标的结构 或机械信息不可用或未提供足够的信息 洞察力以实现高效的图书馆设计。此外，对于许多目标， 尚未确定先导化合物或新的结合基序 想要的。毫不奇怪，在这种情况下，准备工作和 图书馆的筛选不太成功，因为我们可以准备和 仅测试大于 1060 个小值中的无限小部分 理论上可以制备的分子。在此，我们提出 开发一种强大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引导配体 集会。该方法涉及四个连续的、简单的步骤，并且 不依赖先导化合物，也不需要了解其机制或 生物靶标的结构。 (1) 一组潜在的结合元素是 制备其中该组的每个分子必须可溶于水溶液 高浓度且必须包含共同的化学连接基团。 (2) 在高浓度下筛选潜在的结合元件组，以 识别所有与生物相互作用甚至微弱的结合元件 目标。 (3) 制备连接的结合元件的组合文库 由此，结合元件使用共同的化学键连接 通过一组灵活的连接器进行分组。 (4) 组合库 筛选连接的结合元件以鉴定最紧密的结合配体。

项目成果

Design and synthesis of novel inhibitors of gelatinase B.

新型明胶酶B抑制剂的设计与合成。

• DOI: 10.1016/s0960-894x(02)00365-7
• 发表时间: 2002
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Wang,Xueqing;Choe,Youngchool;Craik,CharlesS;Ellman,JonathanA
• 通讯作者: Ellman,JonathanA

The proapoptotic benzodiazepine Bz-423 affects the growth and survival of malignant B cells.

促凋亡苯二氮卓类 Bz-423 影响恶性 B 细胞的生长和存活。

• 发表时间: 2003
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Boitano,Anthony;Ellman,JonathanA;Glick,GaryD;OpipariJr,AnthonyW
• 通讯作者: OpipariJr,AnthonyW

Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.

苯二氮卓诱导的超氧化物信号 B 细胞凋亡：机制洞察和潜在的治疗效用。

• DOI: 10.1172/jci16029
• 发表时间: 2002
• 期刊: The Journal of clinical investigation
• 作者: Blatt,NealB;Bednarski,JeffreyJ;Warner,RoscoeE;Leonetti,Francesco;Johnson,KathrynM;Boitano,Anthony;Yung,Raymond;Richardson,BruceC;Johnson,KentJ;Ellman,JonathanA;OpipariJr,AnthonyW;Glick,GaryD
• 通讯作者: Glick,GaryD

Structure activity studies of a novel cytotoxic benzodiazepine.

新型细胞毒性苯二氮卓类药物的结构活性研究。

• DOI: 10.1016/s0960-894x(03)00683-8
• 发表时间: 2003
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Boitano,Anthony;Emal,CoryD;Leonetti,Francesco;Blatt,NealB;Dineen,ThomasA;Ellman,JonathanA;Roush,WilliamR;Opipari,AnthonyW;Glick,GaryD
• 通讯作者: Glick,GaryD

Tyrosylprotein sulfotransferase inhibitors generated by combinatorial target-guided ligand assembly.

通过组合靶标引导的配体组装产生酪氨酰蛋白磺基转移酶抑制剂。

• DOI: 10.1016/s0960-894x(01)00744-2
• 发表时间: 2002
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Kehoe,JohnW;Maly,DustinJ;Verdugo,DawnE;Armstrong,JoshuaI;Cook,BrianN;Ouyang,Ying-Bin;Moore,KevinL;Ellman,JonathanA;Bertozzi,CarolynR
• 通讯作者: Bertozzi,CarolynR