Editing Combinatorial chemistry (section)

===Deconvolution of libraries cleaved from the solid support===

If the synthesized molecules of a combinatorial library are cleaved from the solid support a soluble mixture forms. In such solution, millions of different compounds may be found. When this synthetic method was developed, it first seemed impossible to identify the molecules, and to find molecules with useful properties. Strategies for identification of the useful components had been developed, however, to solve the problem. All these strategies are based on synthesis and testing of partial libraries. An early iterative strategy was devised by Furka in 1982.<ref name=Furka/> The method was later independently published by Erb et al. under the name "Recursive deconvolution"<ref>Erb E, Janda KD, Brenner S (1994) Recursive deconvolution of combinatorial chemical libraries Proc. Natl Acad Sci.USA 91; 11422-11426.</ref>
[[File:Recursive deconvolution.png|thumb|left|350px|Recursive deconvolution. Blue, yellow and red circles: amino acids, Green circle: solid support]]

====Recursive deconvolution====

The method is made understandable by the figure. A 27-member peptide library is synthesized from three amino acids. After the first (A) and second (B) cycles samples were set aside before mixing them. The products of the third cycle (C) are cleaved down before mixing then are tested for activity. Suppose the group labeled by + sign is active. All members have the red amino acid at the last coupling position (CP). Consequently, the active member also has the red amino acid at the last CP. Then the red amino acid is coupled to the three samples set aside after the second cycle (B) to get samples D. After cleaving, the three E samples are formed. If after testing the sample marked by + is the active one it shows that the blue amino acid occupies the second CP in the active component. Then to the three A samples first the blue then the red amino acid is coupled (F) then tested again after cleaving (G). If the + component proves to be active, the sequence of the active component is determined and shown in H.

====Positional scanning====

Positional scanning was introduced independently by Furka et al.<ref>Furka Á, Sebestyén F, WC 93/24517, 1993.</ref> and Pinilla et al.<ref>Pinilla C, Appel JR, Blanc P, Houghten RA (1993) Rapid identification of high affinity peptide ligands using positional scanning synthetic peptide combinatorial libraries. BioTechniques 13(6); 901-5.</ref> The method is based on the synthesis and testing of series of sublibraries. in which a certain sequence position is occupied by the same amino acid. The figure shows the nine sublibraries (B1-D3) of a full peptide trimer library (A) made from three amino acids. In sublibraries there is a position which is occupied by the same amino acid in all components. In the synthesis of a sublibrary the support is not divided and only one amino acid is coupled to the whole sample. As a result, one position is really occupied by the same amino acid in all components. For example, in the B2 sublibrary position 2 is occupied by the "yellow" amino acid in all the nine components. If in a screening test this sublibrary gives positive answer it means that position 2 in the active peptide is also occupied by the "yellow" amino acid. The amino acid sequence can be determined by testing all the nine (or sometime less) sublibraries. 
[[File:Positional scanning.png|thumb|left|400px|Positional scanning. Full trimer peptide library made from 3 amino acids and its 9 sublibraries. The first row shows the coupling positions.]]
[[File:Full and omission libraries.png|thumb|right|460px|A 27-member tripeptide full library and the three omission libraries. The color circles are amino acids.]]

====Omission libraries====

In omission libraries<ref>Carell TE, Winter A, Rebek J Jr. (1994) A Novel Procedure for the Synthesis of Libraries Containing Small Organic Molecules, Angew Chem Int Ed Engl 33; 2059-2061.</ref><ref>Câmpian E, Peterson M, Saneii HH, Furka Á, (1998) Deconvolution by omission libraries, Bioorg &[ Med Chem Letters 8; 2357-2362.</ref> a certain amino acid is missing from all peptides of the mixture. The figure shows the full library and the three omission libraries. At the top the omitted amino acids are shown. If the omission library gives a negative test the omitted amino acid is present in the active component.