STRATEGIES FOR RAPID DECONVOLUTION OF COMBINATORIAL LIBRARIES - COMPARATIVE-EVALUATION USING A MODEL SYSTEM

Synthesis and testing of complex mixtures maximize the number of compo unds that can be prepared and tested in a combinatorial library. When mixtures of compounds are screened, however, the identity of the compo und(s) selected may depend on the deconvolution procedure employed. Pr eviously, we developed a model system for evaluation of deconvolution procedures and used it to compare pooling strategies for iterative and noniterative deconvolution [Freier et al. J. Med. Chem. 1995, 38, 344 -352]. We have now extended the model studies to include simulations o f procedures with overlapping subsets such as subtractive pooling [Car ell et al. Angew. Chem., Int. Ed. Engl. 1994, 33, 2061-2064], bogus co in pooling [Blake and Litzi-Davis. Bioconjugate Chem. 1992, 3, 510-513 ], and orthogonal pooling [D'Prez et al. J. Am. Chem. Sec. 1995, 117, 5405-5406]. These strategies required synthesis and testing of fewer s ubsets than did the more traditional nonoverlapping iterative strategi es. The compounds identified using simulations of these strategies, ho wever, were not the most active compounds in the library and were subs tantially less active than those identified by simulations of more tra ditional strategies.