Design and Diversity Analysis of Large Combinatorial Libraries Using Cell-Based Methods

Generation of large libraries of small molecules has required a reexamination of the methods chemists use to select their starting materials for synthesis. When a few reagents can be used to generate vast numbers of compounds, selection of an appropriately diverse set of starting materials is important. Since syntheses involve reactions between specific functional groups, it is reasonable to sort reagents by these groups. Then the diversity of the fragments attached to the given reactive functionality may be examined. This diversity may be defined in terms of the biologically relevant properties of a three-dimensional structure. Cell-based methodology can be used to divide reagents into convenient subsets from which representative diverse reagents can be selected for library synthesis. For ECLiPS libraries, analyses of the reagents used in each individual step have proven to be a useful strategy. Further cell-based analyses of the actual libraries in conjunction with biological activity data have shown clustering of actives in the selected diversity spaces.