Editing Combinatorial chemistry (section)

====Encoded combinatorial libraries====

If we deal with a non-peptide organic libraries library it is not as simple to determine the identity of the content of a bead as in the case of a peptide one. In order to circumvent this difficulty methods had been developed to attach to the beads, in parallel with the synthesis of the library, molecules that encode the structure of the compound formed in the bead. 
Ohlmeyer and his colleagues published a binary encoding method<ref>Ohlmeyer MHJ, Swanson RN, Dillard LW, Reader JC, Asouline G, Kobayashi R, Wigler M, Still WC (1993) Complex synthetic chemical libraries indexed with molecular tags, Proc Natl Acad Sci USA 90; 10922-10926.</ref> They used mixtures of 18 tagging molecules that after cleaving them from the beads could be identified by Electron Capture Gas Chromatography. Sarkar et al. described chiral oligomers of pentenoic amides (COPAs) that can be used to construct mass encoded OBOC libraries.<ref>Sarkar M, Pascal BD, Steckler C, Aquino C., Micalizio GC, Kodadek T, Chalmers MJ (1993) Decoding Split and Pool Combinatorial Libraries with Electron Transfer Dissociation Tandem Mass Spectrometry, J Am Soc Mass Spectrom 24(7): 1026-36.</ref> 
Kerr et al. introduced an innovative encoding method<ref>Kerr JM, Banville SC, Zuckermann RN (1993) Encoded Combinatorial Peptide Libraries Containing Non-Natural Amino Acids, J Am Chem. Soc 115; 2529-2531.</ref> An orthogonally protected removable bifunctional linker was attached to the beads. One end of the linker was used to attach the non-natural building blocks of the library while to the other end encoding amino acid triplets were linked. The building blocks were non-natural amino acids and the series of their encoding amino acid triplets could be determined by Edman degradation. The important aspect of this kind of encoding was the possibility to cleave down from the beads the library members together with their attached encoding tags forming a soluble library. The same approach was used by Nikolajev et al. for encoding with peptides.<ref>Nikolaiev V, Stierandová A, Krchnák V, Seligmann B, Lam KS, Salmon SE, Lebl M, (1993) Peptide-encoding for structure determination of nonsequenceable polymers within libraries synthesized and tested on solid-phase supports, Pept Res. 6(3):161-70.</ref> 
In 1992 by Brenner and Lerner introduced DNA sequences to encode the beads of the solid support that proved to be the most successful encoding method.<ref>Brenner S, Lerner RA. (1992) Encoded combinatorial chemistry. Proc Natl Acad Sci USA 89; 5381–5383.</ref>  Nielsen, Brenner and Janda also used the Kerr approach for implementing the DNA encoding<ref>Nielsen J, Brenner S, Janda KD. (1993) Synthetic methods for the implementation of encoded combinatorial chemistry. Journal of the American Chemical Society, 115 (21); 9812–9813.</ref>
In the latest period of time there were important advancements in DNA sequencing. The next generation techniques make it possible to sequence large number of samples in parallel that is very important in screening of DNA encoded libraries. There was another innovation that contributed to the success of DNA encoding. In 2000 Halpin and Harbury omitted the solid support in the split-mix synthesis of the DNA encoded combinatorial libraries and replaced it by the encoding DNA oligomers. In solid phase split and pool synthesis the number of components of libraries can't exceed the number of the beads of the support. By the novel approach of the authors, this restraint was eliminated and made it possible to prepare new compounds in practically unlimited number.<ref>Harbury DR, Halpin DR (2000) WO 00/23458.</ref> The Danish company Nuevolution for example synthesized a DNA encoded library containing 40 trillion! components<ref>B. Halford How DNA-encoded libraries are revolutionizing drug discovery. C&EN 2017, 95, Issue 25.</ref>
The DNA encoded libraries are soluble that makes possible to apply the efficient affinity binding in screening. Some authors apply the DEL for acromim of DNA encoded combinatorial libraries others are using DECL. The latter seems better since in this name the combinatorial nature of these libraries is clearly expressed.
Several types of DNA encoded combinatorial libraries had been introduced and described in the first decade of the present millennium. These libraries are very successfully applied in drug research.
* DNA templated synthesis of combinatorial libraries described in 2001 by Gartner et al.<ref>Gartner ZJ, Tse BN, Grubina RB, Doyon JB, Snyder TM, Liu DR (2004) DNA-Templated Organic Synthesis and Selection of a Library of Macrocycles, Science 305; 1601-1605.</ref>
* Dual pharmacophore DNA encoded combinatorial libraries invented in 2004 by Mlecco et al.<ref>Melkko S, Scheuermann J, Dumelin CE, Neri D (2004) Encoded self-assembling chemical libraries Nat Biotechnol 22; 568-574.</ref>
* Sequence encoded routing published by Harbury Halpin and Harbury in 2004.<ref>Halpin DR, Harbury PB (2004) DNA Display I. Sequence-Encoded Routing of DNA Populations, PLoS Biology 2; 1015-102.</ref>
* Single pharmacophore DNA encoded combinatorial libraries introduced in 2008 by Manocci et al.<ref>Mannocci L, Zhang Y, Scheuermann J, Leimbacher M, De Bellis G, Rizzi E, Dumelin C, Melkko S, and Neri N (2008) High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries, Proc Natl Acad Sci USA 105;17670–17675.</ref>
* DNA encoded combinatorial libraries formed by using yoctoliter-scale reactor published by Hansen et al. in 2009<ref>Hansen MH, Blakskjær P, Petersen LK, Hansen TH, Højfeldt JW, Gothelf KV, HansenNJV (2009) A Yoctoliter-Scale DNA Reactor for Small-Molecule Evolution (2009) J Am Chem Soc 131; 1322-1327.</ref>
Details are found about their synthesis and application in the page [[DNA-encoded chemical library]].
The DNA encoded soluble combinatorial libraries have drawbacks, too. First of all the advantage coming from the use of solid support is completely lost. In addition, the polyionic character of DNA encoding chains limits the utility of non-aqueous solvents in the synthesis. For this reason many laboratories choose to develop DNA compatible reactions for use in the synthesis of DECLs. Quite a few of available ones are already described<ref>Luk KC,  Satz AL (2014) DNA‐Compatible Chemistry in: Goodnow Jr. RA Editor A Handbook for DNA‐Encoded Chemistry: Theory and Applications for Exploring Chemical Space and Drug Discovery, Wiley, pp 67-98.</ref><ref>Satz AL, Cai J, Chen Y,§, Goodnow R, Felix Gruber F, Kowalczyk A, Petersen A, Naderi-Oboodi G, Orzechowski L, Strebel Q (2015) DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries Bioconjugate Chem 26; 1623−1632.</ref><ref>Li Y, Gabriele E, Samain F, Favalli N, Sladojevich F, Scheuermann J, Neri D (2016) Optimized reaction conditions for amide bond formation in DNA-encoded combinatorial libraries, ACS Comb Sci 18(8); 438–443.</ref>