Orthogonal library

As in solid-phase synthesis programs, one of the most challenging problems with solution-phase synthesis is to separate products obtained in the reaction mixtures and identify the compound or compounds with biological potency or some other desirable property. An especially effective technique that has been developed to deal with this problem is called indexed libraries, also known as orthogonal libraries. In this process, each product compound is prepared twice. Analysis then permits identification of the positive part of the compound and the negative part of the compound with the greatest potency. Once these have been determined, it is possible to identify the specific compound most active in the mixture. 

Fig. 5. Orthogonal library format two-set, four-element library.

Screening large pools of compounds has several disadvantages, and often results in missed or false activities. To obviate such limitations, different pooling and structure identification strategies such as orthogonal libraries and binary encoded libraries have been developed and reported to provide examples of bioactive molecules. 

Several other deconvolution methods have been reported. Orthogonal libraries (168), subtractive deconvolution (169), omission libraries (170), bogus coin deconvolution (171), deletion synthesis deconvolution (172), and mutational SURF (Synthetic... 

The deconvolution of orthogonal libraries is based on the fact that each peptide of the library is present in one sublibrary of A and one sublibrary of B, and that particular peptide is the only one these two sublibraries have in common (see Section 4.3.V.3.2.3). Consequently, after having determined the most-active sublibraries in both libraries A and B in a given bioassay, individual active peptides are identified by deciphering the peptide that the active sublibraries of A and B have in common. If more than one sublibrary is active in each library, many individual peptides representing the common peptides of the different sublibrary pairs from both libraries have to be synthesized and tested in order to identify the... 

Combinatorial synthesis towards libraries of compound mixtures can be done either on a solid support or in solution. In both cases an effective decoding strategy is required to extract structural information from the results of the biological assay (see Section 1.4.2.1.2 Deconvolution by Orthogonal Libraries). 

Three deconvolution strategies can be used for the structural determination of the biologically most active compounds in a combinatorial library comprising mixtures of up to several thousand compounds (1) iterative deconvolution [47, 98] (2) deconvolution by positional scanning [99-101] or (3) deconvolution by orthogonal libraries [102-104]. 

The combinatorial synthesis of orthogonal libraries involves the synthesis of two series of sublibraries. In the first series, each of the building blocks An reacts separately with a... 

Figure 1.9. Schematic representation of an orthogonal library synthesized from each of four components A and B. Each column and each row represents a compound mixture consisting of four compounds (for example A1B1 to A1B4). The single compound responsible for the biological activity in the screening is derived from the correlation of two most active mixtures (shaded rows). In this case, A3B1.

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