Divide, couple, and recombine

Two different approaches, the divide, couple and recombine (DCR) method9 (also known as split-resin method8) and the reagent mixture method17 are widely used for the chemical generation of immense mixtures and will be explained here in detail. 

The synthesis of mixture-based libraries in any of the various formats relies on the divide, couple, and recombine paradigm (Fig. 1) to assemble the mixture [13-15], In this method, the solid support is divided into appropriate portions, each portion is coupled... 

Iterative deconvolution is the original deconvolution method and remains quite reliable. The method relies on the synthesis of the library by the divide, couple, and recombine method to prepare a series of mixtures each with one residue of a selected diversity position being unique to each mixture. An active mixture(s) is selected and a resynthesis is performed whereby a second diversity position is defined. This is repeated until the resynthesis produces individual compounds. The highly active individual compounds this yields are the actives observed in the original active pool(s) ofthe library. The iterative method has been modeled by computer simulations. The results reported indicate that, even when accounting for experimental variability, an iterative deconvolution will converge to a molecule(s) that is the most active or very close to the most active (within 1 kcal) even for very large pools ( 65 000 compounds/pool) [18,19],... 

A follow-on concept to the one-bead-one-compound concept was recently published as a library of libraries , whereby the authors demonstrated, for peptides, the idea of one-bead-one-motif [83], For linear peptides, this method assumes that some positions are important for structure and some are important for contact with the target. The library construction is accomplished by combining elements of an iterative library with a parallel array library. The construction of the library breaks the structure down into positions defined as structural positions and motif (pharmacophore) positions. The structural positions are built with mixtures of building blocks and the motif positions are constructed through the divide, couple, and recombine procedure. The results reported showed that peptide binding motifs could be identified that reproduced known motifs. 

Furka and co-workers pioneered the split-pool synthesis method [19-22] for the synthesis of large peptide libraries in 1988 this approach is termed divide, couple, and recombine synthesis by other workers [44-47]. 

Figure 2 (a) The divide, couple, and recombine method of library synthesis, (b) The reagent mixture approach. 

In addition to the parallel preparation of individual peptide sequences, simultaneous multiple peptide synthesis is used together with the divide, couple, recombine method (9) (also termed spiit-and-mix (10) or porlioning-and-mixing (11)) to prepare peptide combinatorial libraries containing mixtures of thousands to millions of peptides (12). 

Another approach that has been used to generate combinatorial libraries of peptides is the split synthesis method [102-104]. This technique involves dividing the resin support into n equal fractions, coupling each fraction with a single activated monomer (or in some cases, a small number of monomers), and then recombining the fractions (Fig. 14). Iteration for x cycles leads to a stochastic population of rf peptides. This approach has been used in conjunc-... 

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