Strategies for rapid deconvolution of combinational libraries: comparative evaluation using a model system.
Synthesis and testing of complex mixtures maximize the number of compounds that can be prepared and tested in a combinatorial library. When mixtures of compounds are screened, however, the identity of the compound(s) selected may depend on the deconvolution procedure employed. Previously, 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 of procedures with overlapping subsets such as subtractive pooling [Carell et al. Angew, Chem., Int. Ed. Engl. 1994, 33, 2061-2064], bogus coin pooling [Blake and Litzi-Davis. Bioconjugate Chem. 1992, 3, 510-513], and orthogonal pooling [D'Prez et al. J. Am. Chem. Soc. 1995, 117, 5405-5406]. These strategies required synthesis and testing of fewer subsets than did the more traditional nonoverlapping iterative strategies. The compounds identified using simulations of these strategies, however, were not the most active compounds in the library and were substantially less active than those identified by simulations of more traditional strategies.
Konings
D A
DA
ISIS Pharmaceuticals, Carlsbad, California 92008, USA.
Wyatt
J R
JR
Ecker
D J
DJ
Freier
S M
SM
D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D009010:Monte Carlo Method; D009841:Oligonucleotides / Q000737:chemistry; D019151:Peptide Library; D012313:RNA / Q000737:chemistry*
D009841:Oligonucleotides; D019151:Peptide Library; D012313:RNA