Needs of the Drug Discovery Process

2 Split/Pool Method for Creating Combinatorial Libraries 

The split/pool method for the preparation of combinatorial libraries is outlined in Fig. 1. 

In 1985, Houghten [11] used this method in his tea bag approach described in section 3.4.4.2 of this chapter. As an elemental synthesis unit, instead of individual resin beads, he used small batches of resin packed into a polypropylene mesh. Furka [12,13] described the split/pool methodology for the synthesis of peptides. The peptides were cleaved and analyzed as mixtures and separated by HPLC as a rapid method for multiple peptide synthesis. In his work, Furka did not suggest explicitly to cleave individual compounds from individual beads. This seemingly obvious idea was recognized by Lam [14,15]. Split/pool synthesis was further developed and widely used by many others working in-the field of combinatorial chemistry [16]. The new Journal of Combinatorial Chemistry published a very interesting historical perspective on the major events in this field [17], 

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The scope of the methods practiced in modern combinatorial chemistry is very large. Compounds are synthesized in solution and on solid phase, in a wide range of quantities large and small, encoded and unencoded libraries fit different needs of the drug discovery process. Chemistry optimization is more demanding in the case of combinatorial chemistry. Optimal conditions for the reliable and high-yield synthesis of all library members should be discovered through experimentation. 

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