Encoded combinatorial library

The simplest strategy for determining the structure of a compound prepared on a single bead is encoding. This indirect method of structure determination can be used both with testing methods that involve bead bound ligands as well as with solution methods that use material removed from the solid support. 

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E. A. An affinity selection-mass spectrometry method for the identification of small molecule ligands from self-encoded combinatorial libraries, discovery of a novel antagonist of E. coli dihydrofolate reductase. Int. J. Mass. Spectrom. 2004, 238, 77-83. 

Still, W. C. Discovery of sequence-selective peptide binding by synthetic receptors using encoded combinatorial libraries. Acc. Chem. Res. 1996,29,155-163. 

Burbaum JJ, Ohlmeyer MHJ, Reader JC, Henderson I, Dillard LW, Li G, Randle TL, Sigal NH, Chelsky D, Baldwin JJ. A paradigm for drug discovery employing encoded combinatorial libraries. Proc Natl Acad Sci USA 1995 92 6027-6031. 

Moran, E. J. Sarshar, S. Cargill, J. F. Shahbaz, M. M. Lio, A. M. Mjalli, A. M. M. Armstrong, R. W. Radio Frequency Tag Encoded Combinatorial Library Method for the Discovery of Tripeptide-Substituted Cinnamic Acid Inhibitors of the Protein Tyrosine Phosphatase PTP1B, J. Am. Chem. Soc. 1995, 777,10787. 

Lane, S. J., and Pipe, A. (2000). Single bead and hard tag decoding using accurate isotopic difference target analysis-encoded combinatorial libraries. Rapid Commun. Mass Spectrom. 14 782-793. 

Annis D.A., Athanasopoulos J., Curran P.J., Felsch J.S., Kalghatgi K., Lee W.H., Nash H.M., Orminati J.P.A., Rosner K.E., Shipps GW., Thaddupathy G.R.A., Tyler A.N., Vilenchik L., Wagner C.R., Wintner E.A., An affinity selection-mass spectrometry method for the identification of small molecule ligands from self-encoded combinatorial libraries. Discovery of a novel antagonist of E. coli dihydrofolate reductase Int. J. Mass Spectrom. 2004, 238, 77-83. 

Wagner, D. S. Markworth, C. J. Wagner, C. D. Schoenen, E J. Rewerts, C. E. Kay, B. K. Geysen, H. M. 1998. Ration encoding combinatorial libraries with stable isotopes and their utility in pharmaceutical research. Comb. Chem. High Throughput Screen, 1,143-153. 

Moran EJ, Sarshar S, Cargill JF, Shahbaz M, Lio A, Mjalli AMM, Armstrong RW, Radiofrequency tog encoded combinatorial library method for the discovery of tripeptide-substituted cinnamic acid inhibitors of the protein tyrosine phosphatase PTPSB J. Am. Chem. Soc., 117 10787-1788, 1995. 

Nielsen J, Janda KD, Toward chemical implementation of encoded combinatorial libraries, Methods Meth. Enzymol., 6 361-371, 1994. 

Vagner J, Barany G, Lam KS, Krchnak V, Sepetov NF, Ostrem JA, Strop P, Lebl M, Enzyme-mediated spatial segregation on individual polymeric support beads application to generation and screening of encoded combinatorial libraries, Proc. Nat. Acad. Sci. USA, 93 8194-8199, 1996. 

Burger MT, Still WC, Synthetic ionophores. Encoded combinatorial libraries of cyclen-based receptors for Cu(2+) and Co(2+), J. Org. Chem., 60 7382-7383, 1995. 

Carroll CD, Johnson TO, Tao S, Lauri G, Orlowski M, Gluzman IY, Goldnerg DE, Dolle RE, Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D, Bioorg. Med. Chem. Lett., 8 2315-2320, 1998. 

Schullek JR, Butler JH, Ni ZJ, Chen D, Yuan ZY, A high-density screening format for encoded combinatorial libraries assay miniaturization and its application to enzymatic reactions, Anal. Biochem., 246 20-29, 1997. 

Fitch WL, Baer TA, Chen W, Holden F, Holmes CP, Maclean D, Shah N, Sullivan E, Tang M, Wayboum P, Fischer SM, Miller CA, Snyder LR, Improved methods for encoding and decoding dialkylamine-encoded combinatorial libraries, J. Comb. Chem., 1 188-194, 1999. 

Rahman SS, Busby DJ, Lee DC, Infrared and Raman spectra of a single resin bead for analysis of solid-phase reactions and use in encoding combinatorial libraries, J. Org. Chem., 63 6196-6199, 1998. 

Armstrong RW, Tempest PA, Cargill JF, Microchip encoded combinatorial libraries, Generation of a spatially encoded library from a pool synthesis. Chimia, 50 258-260, 1996. 

One of the most powerful and systematic methods for the synthesis of an encoded combinatorial library is the so called split synthesis procedure (Fig. 2) [4]. 

Fitch et al. has recently published a new cation-exchange LC/MS method for decoding dialkylamine-encoded combinatorial libraries without the necessity to derivatise [35] and using a new tag set designed to contain unique masses for each code. We have concentrated on the development of new chromatographic and mass spectrometric methods that utilise the rapid dansyl derivatisation to improve specificity as well as chromatographic reproducibility and resolution. 

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