Iterative resynthesis

A number of modifications have been reported in order to address these complications. Janda has noted that during the first split-pool procedure, resin can be saved at each cycle immediately prior to resin pooling.This resin can later be used as an intermediate in the iterative resynthesis and deconvolution procedure (recursive deconvolution) [109]. This results in considerable savings in time and effort. 

There are several ways to deconvolute or identify the individual active compounds in an active mixture. These include iterative resynthesis and the synthesis of overlapping mixtures, such as the positional scanning method of Houghten et al." In iterative resynthesis, the most active pools are resynthesized as several smaller subpools with a variable position resolved. This process is repeated until every position has been resolved and individual active compounds have been made. In Houghten s method, the complete library is... 

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],... 

The original iterative method for deconvolution remains robust and highly useful. However, there are opinions that the resynthesis aspect makes this deconvolution slow to yield individual hits, although no study is known that comparatively quantifies this. In order to overcome this perception, a number of research groups are actively developing additional deconvolution methods for mixture-based libraries. 

Although not identical, both the orthogonal and positional scan formatted libraries share the features that all mixtures are made at the start of the library process and only individual compound synthesis is required after the first screening of mixtures. This is an extra initial effort with regard to the synthesis of mixtures when compared to an iterative method. The advantage is that no intermediate mixture syntheses will be required. If prepared in sufficient quantity, the library can be screened over a large number of assays, and the added effort of initial mixture syntheses will be translated into an efficiency in deconvolution relative to the continual resynthesis of mixtures with iterative deconvolution. 

Deconvolution is one technique for finding the active component. A review of various deconvolution methods has been published." In the iterative deconvolution strategy, compound pools are screened, active pools are identified and then sublibraries (i.e., smaller pools) are resynthesized and rescreened. Suppose that the central column of nine trimers in one pot in Figure 4 is active. All those compounds have a terminal B. The object is now to make three mixtures of three compounds to determine whether the most active mixture has A, B, or C in the middle. Resynthesis is carried out, adding B to the dimers to make three pots containing BAA, BAB, and BAG in the first, BBA, BBC, and BBB in the second, and BCA, BCB, and BCC in the third. (Some users retain samples of the dimer... 

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