ZINC-DIRECTED INHIBITORS FOR ZINC PROTEINASES

Zinc proteinases have been recognized as a distinct class of proteolyt ic enzymes in which at least one ion of zinc is involved directly in c atalysis. This family includes a growing number of biologically import ant enzymes which are attractive targets for rational drug design. In this paper we examine the special features of the zinc binding environ ment of these enzymes in order to gain information which could be usef ul in the preparation of 'zinc-directed' selective inhibitors. Carboxy peptidase A (CPA) is presented as a model for one class of zinc protei nases, and the active-site zinc and its interactions are examined with the primary focus on geometrical considerations. The three-dimensiona l structure of the native and apoenzyme are discussed, together with t he high-resolution structure of several enzyme-inhibitor complexes. Th is paper will first present a structural analysis of CPA derivatives a nd then discuss a series of zinc model compounds which have been prepa red and characterized in order to examine the ligand and geometrical p references of the zinc in an unstrained system. X-ray crystallography (macromolecular and small molecule) is the main experimental method us ed for the structural analyses, while complementary computational meth ods have been used for the examination of electrostatic potentials. Th e results from the various experimental efforts are assembled in order to draw general conclusions on the potential use of the zinc ion as t he primary target for inhibitor binding. The results of these studies suggest that the zinc ion is important for both the binding and the ca talytic activation of the substrate as well as for stabilization of th e tetrahedral reaction intermediate.