RATIONAL DRUG DESIGN BASED ON CHEMICAL MECHANISM

基于化学机理的合理药物设计

• 批准号: 3167983
• 负责人: JAMES K COWARD
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1992-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3167983
• 关键词: DNA replication; RNA biosynthesis; adenosine triphosphate; alkylation; antineoplastics; asparagine; chemical structure function; drug design /synthesis /production; drug metabolism; enzyme inhibitors; folate; glutamine; macromolecule; messenger RNA; methionine; neoplasm /cancer pharmacology; nutrition related tag; phosphorylation; polyamines; polyglutamates; protein kinase; transfer RNA

We plan to continue our efforts in the synthesis of potent and specific enzyme inhibitors, based on enzyme mechanism data obtained in our laboratory, and from the literature. We plan to further exploit our discovery that 4-fluoroglutamate (FGlu) acts as a chain terminating inhibitor of folylopolyglutamate synthetase. We will synthesize FGlu-containing folates for studies which will complement our preliminary and ongoing studies with fluoromethotrexate. We will synthesize a new series of compounds designed to inhibit Gamma-glutamyl hydrolase, the enzyme responsible for hydrolytic breakdown of the folylpoly glutamates. We will continue our synthetic efforts aimed at synthesizing a complex acetylenic nucleoside amino acid, designed as a specific multisubstrate adduct inhibitor of catechol 0-methyltransferase. We plan to extend the newly developed synthetic techniques to the synthesis of an analogous multisubstrate adduct inhibitor of adenine N6-methyltransferase. We will complete our synthesis of a series of ATP-Gamma-peptidyl esters, designed to inhibit c-AMP-dependent protein kinase. In all these areas of research, completion of the synthetic work will allow us to assess the efficacy of these new compounds in cell-free (enzyme) systems, as well as in cultured mammalian cells. The biochemical and cell biology work will be done in our laboratories, as well as in collaborative efforts with others. This method of covering the broad areas of expertise required for careful experimental design has served us well in the past with our modulators of spermidine biosynthesis and folylpolyglutamate biosynthesis. By this research, we intend to synthesize a series of potent and specific inhibitors of selected enzymes which we feel are critical for cell function. We will be able to answer specific questions about the energetics of substrate vs. transition-state binding in enzyme catalysis, a subject of considerable importance in understanding how enzymes catalyze reactions in the living cell. In a more applied sense, we will be developing a method for the rational design of new enzyme inhibitors as potential drugs, based on the mechanism of action of the enzyme under study.

我们计划继续努力综合有效和特定 酶抑制剂，基于在我们的酶机制数据 实验室和文献。 我们计划进一步利用我们的 发现4-氟谷氨酸（FGLU）充当链条 Folylypopolyglutamate合成酶的抑制剂。 我们将合成 含FGLU的叶酸进行研究，这将补充我们的初步 以及正在进行的氟硫代酯研究。 我们将合成一个新的 一系列旨在抑制γ-谷氨酰水解酶的化合物， 负责谷氨酸谷氨酸水解分解的酶。 我们将继续旨在综合复杂的综合努力 乙酰基因核苷氨基酸，设计为特定的多卵石 儿茶酚0-甲基转移酶的加合物抑制剂。 我们计划扩展 新开发的合成技术与类似的合成 腺嘌呤N6-甲基转移酶的多底物加合物抑制剂。 我们将 完成我们设计的一系列ATP-gamma-肽基酯的合成 抑制C-AMP依赖性蛋白激酶。 在所有这些研究领域， 合成工作的完成将使我们能够评估 这些新化合物在无细胞（酶）系统以及培养的 哺乳动物细胞。 生化和细胞生物学工作将在我们的 实验室以及与他人的合作努力。 此方法 涵盖仔细实验所需的广泛专业知识领域 设计与精子调节剂过去对我们有好处 生物合成和叶基聚谷氨酸生物合成。 通过这项研究，我们 打算合成一系列选定的有效抑制剂 我们认为对细胞功能至关重要的酶。 我们将能够 回答有关基材VS的能量学的具体问题。 酶催化中的过渡状态结合，这是一个相当多的主题 重要性在理解酶如何催化生活中的反应 细胞。 从更应用的意义上讲，我们将开发一种方法 基于 研究酶的作用机理。