ABSTRACT
The advent of high throughput screening (HTS) has created a need for an ever-increasing number of compounds. Combinatorial chemistry, which originated in the field of peptide chemistry, represents a major breakthrough for HTS. Combinatorial chemistry is the synthetic process in which a particular set of building blocks or precursors are used to prepare all possible permutations of a given compound type (1–4). The powerful advantage of combinatorial chemistry comes from its ability to rapidly generate large numbers of novel compounds for testing, and is centered on the use of solid phase synthesis techniques (5). The first reports of the array synthesis of large numbers of individual compounds (initially peptides) in a parallel synthesis mode was reported in 1984 and 1985 (6, 7). Following an initial report (8), the first practical solution-based and immobilized bead-based combinatorial libraries were presented in 1991 (9, 10). The presentation formats for combinatorial libraries of all types of compounds now vary from discrete compound arrays (either on supports (11) or as individual soluble compounds (12, 13)) to complex mixtures of compounds (either on supports (10) or as soluble mixtures (9, 14–16). Compound array synthesis methods (6, 8, 11–13) for preparing larger compound libraries are the smallest but first logical step beyond traditional “one at a time” synthesis that has developed to keep pace with HTS capabilities. The systematic generation of mixtures of compounds ranging in number from hundreds of thousands to millions has been clearly demonstrated and shown to be broadly useful for the identification of active individual compounds (9, 10, 17–21). The method, arrays or mixtures to be utilized in a given HTS situation will be decided in part by the philosophical and practical questions centered on how far one can deviate from traditional screening tenets (i.e., one soluble compound per assay measurement) while still having confidence that the results parallel those which would be attained with traditional screening. The use of mixtures is based on the fact that the results generated from screening the library mixtures (by well-controlled procedures) closesly parallel the 156results that would be attained if one individually tested the compounds comprising the mixture (14,22).
