RATIONAL DRUG DESIGN BASED ON CHEMICAL MECHANISM

我们计划继续努力合成有效的和特定的 酶抑制剂，基于我们的酶机制数据 实验室，并从文献中。我们计划进一步开发我们的 4-氟谷氨酸(FGlu)作为链终止剂的发现 叶基多谷氨酸合成酶的抑制剂。我们将综合 含FGlu的叶酸用于研究，这将补充我们的初步 以及正在进行的氟甲氨蝶呤研究。我们将合成一种新的 一系列旨在抑制伽马-谷氨酰水解酶的化合物 负责叶基聚谷氨酸的水解性分解的酶。 我们将继续我们的合成努力，旨在合成一种复合体 乙酰核苷氨基酸，设计为一种特殊的多底物 邻苯二酚0-甲基转移酶加合物抑制剂。我们计划延长 新开发的合成技术用于合成一种类似物 腺嘌呤N6-甲基转移酶的多底物加合物抑制物。我们会 完成一系列三磷酸腺苷-伽玛-肽基酯的合成，设计 抑制c-AMP依赖的蛋白激酶。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)系统中以及在培养的 哺乳动物细胞。生化和细胞生物学的工作将在我们的 在实验室，以及在与其他机构的协作努力中。这种方法 涵盖仔细实验所需的广泛专业知识领域 过去，我们的亚精胺调节器设计得很好。 生物合成和叶基多谷氨酸的生物合成。通过这项研究，我们 打算合成一系列有效和特异的选定的抑制剂 我们认为对细胞功能至关重要的酶。我们将能够 回答有关底物与 酶催化中的过渡态结合是一个相当重要的课题 了解酶如何在生物中催化反应的重要性 手机。在更实用的意义上，我们将开发一种用于 合理设计新的酶抑制剂作为潜在的药物 该酶的作用机制正在研究中。

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.