DISCOVERY OF ENZYME-INHIBITORS THROUGH COMBINATORIAL CHEMISTRY

This review serves to highlight the recent examples of combinatoric me thodology as applied to the discovery and optimization of enzyme inhib itors. Early research efforts focused on the identification of polypep tides from libraries as inhibitors of proteases. As solution- and soli d-phase chemistries gain in sophistication, libraries containing less peptidic structural motifs have been created. A recurring design strat agem relies on the synthesis of libraries incorporating pharmacophores with known affinity for the target enzyme. Screening of these structu re-based libraries has led to the discovery of small-molecule inhibito rs of both proteolytic and non-proteolytic enzymes alike. Two tables a re provided listing the enzyme targeted libraries through 1996. A name , generic structure and size is given for each library citation, accom panied by the enzyme screen and the structure and potency of the most active library member.