Computer Aided Analysis of Split and Mix Combinatorial Libraries.

Abstract

Combinatorial chemistry using split and pool synthesis involves making and testing mixtures of compounds in pools which are subsets of the larger compound collection. These subsets are created during the synthesis of the collection through a resin splitting and mixing method. Tests are conducted on each of the final pools of mixtures and the individual compounds within a mixture of interest are then identified through some deconvolution scheme, originally involving selective re-synthesis. It is possible that different schemes for splitting and mixing will have different consequences on the overall effort necessary to deconvolute interesting mixtures. The evaluation of different protocols of splitting and mixing involves consideration of more possibilities than can be exhaustively or optimally determined manually in a realistic time frame for most compound collections. We present herein a computational scheme to aid in this analysis. The approach exhaustively examines possible splitting and mixing strategies for the interrelated values of total library size, number of combinatorial steps, number of reaction vessels, and number of compounds per final pool. Weighting factors may be introduced into the various steps. The resulting complete list of splitting and mixing options is scored based on a variable weighting strategy for the total effort of synthesis and deconvolution. The results indicate the splitting/mixing strategy used has an impact on overall efficiency and should be considered in the design of compound libraries.