RECENT ADVANCES IN THE GENERATION OF CHEMICAL DIVERSITY LIBRARIES

In recent years, screening in combination with a diverse compound coll ection has become a powerful method for discovering leads for the ever -increasing number of new biologically active peptides, proteins, rece ptors, and enzymes discovered continually. As a result, the rapid gene ration and screening of compound libraries (collection) have recently become important major tools in the search for novel lead structures. Diverse collections of compounds have been acquired by many strategies ; these include (1) natural products from plants, fermentation, marine organisms, insect toxins, and ethnic pharmacotherapies; (2) recombina nt randomized peptide libraries (often referred to a biological divers ity); (3) multiple peptide synthesis; and (4) non-peptidic synthetic l ibraries. The present review provides an overview of the recent advanc es in the filed of peptide and non-peptidic synthetic libraries. the p rogress made thus far is broadly divided into two categories: (1) Amid e based libraries. These libraries share the concepts of the peptide l ibrary strategies; much of the referenced work thus refers to peptides , reflecting the bias of the literature to date. (2) Non-amide based l ibraries. This promising technology combines solid phase synthesis wit h classical organic synthesis to provide large numbers of compounds wi th desirable bioavailability and pharmacokinetics for screening. The b asic premise behind the second approach is that the high affinity liga nds, when identified, will be much more likely to become useful therap eutic agents than the compounds discovered from amide based libraries. Synthesizing small heterocyclic ring systems that use ligands of dive rse biological activity via combinatorial strategies is a fast develop ing branch of medicinal chemistry. We are at an early state in the dev elopment of combinatorial chemistry. However, this dramatic convergenc e of technologies represents a fundamental advance in medicinal chemis try and promises to play a major role in future drug discovery efforts . (C) 1994 Wiley-Liss, Inc.