RATIONAL DRUG DESIGN BASED ON CHEMICAL MECHANISM

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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.