RATIONAL DRUG DESIGN BASED ON CHEMICAL MECHANISM

我们计划继续努力， 酶抑制剂，根据酶机制的数据，在我们的 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）作为链终止剂 叶酸聚谷氨酸合成酶抑制剂。 我们将合成 含FGlu叶酸的研究将补充我们的初步研究， 和正在进行的氟甲氨蝶呤研究。 我们将合成一种新的 设计用于抑制γ-谷氨酰水解酶的一系列化合物， 负责叶酰聚谷氨酸水解分解的酶。 我们将继续我们的综合努力，旨在合成一个复杂的 炔属核苷氨基酸，设计为特异性多底物 邻苯二酚0-甲基转移酶的加合物抑制剂。 我们计划延长 新开发的合成技术来合成类似物 腺嘌呤N6-甲基转移酶的多底物加合物抑制剂。 我们将 完成了一系列ATP-γ-肽基酯的合成， 抑制cAMP依赖性蛋白激酶。 在所有这些研究领域中， 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 生物化学和细胞生物学工作将在我们的 实验室，以及与他人的合作。 该方法 涵盖了仔细的实验所需的广泛的专业知识领域， 设计在过去的亚精胺调节剂中很好地为我们服务， 生物合成和叶酰聚谷氨酸生物合成。 通过这项研究，我们 旨在合成一系列有效和特异性抑制剂， 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， 理解酶如何催化生物反应的重要性 cell. 从更实际的意义上讲，我们将开发一种方法， 合理设计新的酶抑制剂作为潜在的药物，基于 研究中的酶的作用机制。

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.