SOLID PHASE INTERATIVE BIOCATALYSIS FOR DRUG DISCOVERY

药物发现的固相交互式生物催化

• 批准号: 2718047
• 负责人: Douglas S Clark
• 金额: $ 10万
• 依托单位: ALBANY MOLECULAR RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2718047
• 关键词: antineoplastics; brefeldin A; catalyst; combinatorial chemistry; doxorubicin; drug discovery /isolation; endopeptidases; enzyme activity; solid state; technology /technique development

DESCRIPTION (Adapted from the application): The identification of new drug candidates and subsequent synthesis of large numbers of new derivatives are crucial, yet time-consuming and expensive, steps in the development of drugs with optimal biological activity. The objective of this two-phase program is the development of solid-phase combinatorial biocatalysis as a new and versatile method for rapidly generating libraries of molecules from which biologically active compounds, such as anticancer agents and other types of drugs, can be obtained. The specific aims of Phase I are: 1. Attach the anticancer compound doxorubicin to a solid support and implement strategies for enzymatic release of doxorubicin derivatives from the support; 2. Identify enzymes with reactivity against doxorubicin in solution through application of high-throughput screens; 3. Apply existing methods of protease solubilization in organic solvents to different enzyme classes for modification of substrates attached to solid supports; 4. Modify solid-supported doxorubicin using enzymes dissolved in both aqueous and organic media. This research represents a collaboration between EnzyMed, a division of Albany Molecular Research, Inc., in Iowa City, Iowa, and researchers at the University of California Berkeley, and Rensselaer Polytechnic Institute. The focus of Phase I is to develop the basic tools of solid-phase biocatalytic combinatorial chemistry. In Phase II the applicant will expand upon these tools to generate and screen libraries of natural product derivatives for anticancer activity. PROPOSED COMMERCIAL APPLICATION: The proposed commercial application of solid-phase combinatorial biocatalysis is as a new method for generating pharmaceuticals and other high-value compounds. New doxorubicin derivatives may also have commercial applications as anticancer drugs and as therapeutics against other diseases.

描述（改编自申请）：新药鉴定 候选化合物和随后大量新衍生物的合成， 这是药物开发过程中至关重要但又耗时昂贵的步骤， 具有最佳的生物活性。这个两阶段计划的目标是 固相组合生物催化作为一种新的， 用于快速产生分子文库的通用方法， 生物活性化合物，如抗癌剂和其它类型的 药物是可以获得的。第一阶段的具体目标是： 1.将抗癌化合物多柔比星连接到固体支持物上， 从载体酶促释放多柔比星衍生物的策略; 2.通过以下方法鉴定对溶液中的阿霉素具有反应性的酶： 高通量筛选的应用; 3.将现有的蛋白酶溶解在有机溶剂中的方法应用于 用于修饰附着在固体上的底物的不同酶种类 支持; 4.使用溶解在两种水溶液中的酶修饰固体支持的阿霉素 有机媒介。 这项研究代表了奥尔巴尼的一个部门， 分子研究公司， 在爱荷华州的爱荷华州市， 加州伯克利和伦斯勒理工学院。第一阶段的重点是 开发固相生物催化组合化学的基本工具。在 第二阶段，申请人将扩展这些工具，以生成和筛选 用于抗癌活性的天然产物衍生物的文库。 拟定商业应用： 提出的固相组合生物催化的商业应用是 作为生产药物和其他高价值化合物的新方法。 新的阿霉素衍生物也可能具有抗癌的商业应用 药物和治疗其他疾病。

项目成果

Active-site motions and polarity enhance catalytic turnover of hydrated subtilisin dissolved in organic solvents.

• DOI: 10.1021/ja806996q
• 发表时间: 2009-04-01
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Hudson, Elton P.;Eppler, Ross K.;Beaudoin, Julianne M.;Dordick, Jonathan S.;Reimer, Jeffrey A.;Clark, Douglas S.
• 通讯作者: Clark, Douglas S.

Two-Step Enzymatic Modification of Solid-Supported Bergenin in Aqueous and Organic Media.

水性和有机介质中固载岩白菜素的两步酶改性。

• DOI: 10.1016/j.tetlet.2009.12.119
• 发表时间: 2010
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Akbar,Umar;Shin,Dong-Sik;Schneider,Elizabeth;Dordick,JonathanS;Clark,DouglasS
• 通讯作者: Clark,DouglasS