The discovery of new therapeutic drugs is tightly coupled with the design of specific, potent enzyme inhibitors. Many zinc-containing hydrolytic enzymes are of biomedical linterest. These enzymes include the collagenases, angiotensin-converting enzyme, lactamases, and enkephalinases. The zinc hydrolase aminoacylase I (EC3.5.1.14) has relatively simple substrate structural requirements. Modest synthetic work is needed to prepare its substrates, N-acyl-L-amino acids, and presumably its inhibitors. The goal of this project is to use aminoacylass I as a good general model of zinc hydrolase enzymes in order to compare the potency of three classes of inhibitors. The inhibitor classes are the phosphonamidates I, the thionophosphonamidates II, and the sulfonamides IIII, where R1 - CH3 and NMR2 is derived from the common L amino acids. The inhibitory center of each of the proposed classes of inhibitors not only resembles a transition state or intermediate of the enzyme's catalytic function, but also contains a potentially powerful ligand of zinc. Of these classes of compounds, the thionophosphonamidates II are untested as inhibitors of any zinc hydrolase. Little attention has been paid to sulfonamides III as inhibitors of zinc hydrolases. The proposed research will evaluate the inhibitory potential of the functionalities of interest as well as examine the role of the interaction of the amino acid side chains of the inhibitors with binding sites of the enzyme. This study could provide or suggest new, easily accessible inhibitory centers for inhibitors of zinc hydrolases. Augmentation of the structure of the best inhibitory centers in order to meet the specificity demands of a specific enzyme could result in inhibitors that are more effective and more specific in thwarting the action of biomedically important zinc hydrolases than are presently available.
