Abstract
Libraries encoded with electrophoric tags present a uniquechallenge with respect to library quality control and characterization. Libraries are prepared on Tentagel resin in 200-fold redundancy wherein each resin particle containsone compound per one tag set. The amount of compound presenton the bead is ca. 200–500 pmole while tag levels are estimatedat 0.5–1 pmol/bead. Several quality control protocols have been developed in order to accurately estimate bead yield andpurity for the entire library, ensure high tag fidelity, andto determine the overall performance of individual synthons. This review provides a unique, collective portrait of Pharmacopeia's approach in assessing the quality of librariesprepared using its molecular encoding technology.
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(a) Baldwin, J.J. and Horlbeck, E.G., U.S. Patent 5 663 046, 1997. (b) Baldwin, J.J., Burbaum, J.J., Henderson, I. and Ohlmeyer, M.H.J., Synthesis of a small molecule combinatorial library encoded with molecular tags. J. Am. Chem. Soc., 117 (1995) 5588–5589. (c) Chabala, J.C., Baldwin, J.J., Burbaum, J.J., Chelsky, D., Dillard, L., Henderson, I., Li, G., Ohlmeyer, M.H.J. and Randle, T.L., Binary encoded small-molecule libraries in drug discovery and optimization. Perspect. Drug Discovery Des., 2 (1995) 305–318. (d) Baldwin, J.J., Burbaum, J.J., Chelsky, D., Dillard, L.W., Henderson, I., Li, G., Ohlmeyer, M.H.J., Randle, T.L. and Reader, J.C., Combinatorial libraries encoded with electrophoric tags. Eur. J. Med. Chem., 30 (1995) 349s-58s. (e) Burbaum, J.J., Ohlmeyer, M.H.J., Reader, J.C., Henderson, I., Dillard, Lawrence W., Li, G., Randle, T.L., Sigal, N.H., Chelsky, D. and Baldwin, J.J., A paradigm for drug discovery employing encoded combinatorial libraries. Proc. Natl. Acad. Sci. U.S.A., (1995) 6027–6031. (f) Chabala, J.C., Solid-phase combinatorial chemistry and novel tagging methods for identifying leads. Curr. Opin. Biotechnol., 6 (1995) 632–639. (g) Baldwin, J.J. and Henderson, I., Encoded split synthesis and solid-phase synthetic methodology. Med. Res. Rev., 16 (1996) 391–405. (h) Baldwin, J.J., Design, synthesis and use of binary encoded synthetic chemical libraries. Mol. Diversity, 2 (1996) 81–88. (i) Baldwin, J.J., Kirk, G.L., Dillard, L.W. and Connelly, J.A., Design, synthesis, and preparation of an encoded small molecular library for a wide variety of 96-well based bioassays. Methods Mol. Cellular Biol., 6 (1996) 74–88. (j) Baldwin, J.J. and Dolle, R.E., Deconvolution methods in solid-phase synthesis. Annu. Rep. Comb. Chem. Mol. Diversity, 1 (1997) 287–297. (k) Rokosz, L., Sigal, N.H., Burbaum, J.J., Chelsky, D., Dillard, L.W., Henderson, I., Li, G., Ohlmeyer, M.H.J., Randle, T.L. and Reader, J.C., Synthesis of binary encoded small molecule libraries and their application to drug discovery and optimization. Innovation Perspect. Solid Phase Synth. Comb. Libr., Collect. Pap., Int. Symp., 4th Meeting Date 1995, Epton, R. (Ed.) Mayflower Scientific: Birmingham, U.K., 1996, pp. 101–106. (l) Baldwin, J.J. and Henderson, I., Synthesis of encoded small molecule combinatorial libraries via ECLiPS. In High Throughput Screening, Gordon, E.M. and Kerwin Jr., J.F., (Eds.) Dekker, NY, 1997, pp. 167–190. (m) Baldwin, J.J., Small molecule libraries: Overview of issues and strategies in library design. In Comb. Chem. Mol. Diversity Drug Discovery, Gordon, E.M. and Kerwin Jr., J.F. (Eds.),Wiley-Liss, NY, 1998, pp. 181–188.
(a) Ohlmeyer. M.H.J., Swanson, R.N., Dillard, L.W., Reader, J.C., Asouline, G., Kobayashi, R., Wigler, M. and Still, W.C., Complex synthetic chemical libraries indexed with molecular tags. Proc. Natl. Acad. Sci. U.S.A., 90 (1993) 10922–10926. (b) Nestler, H.P., Bartlett, P.A. and Still, W. Clark, A GeneralMethod for Molecular Tagging of Encoded Combinatorial Chemistry Libraries. J. Org. Chem., 59 (1994) 4723–4724.
(a) Appell, K.C., Chung, T.D.Y., Ohlmeyer, M.J.H., Sigal, N.H., Baldwin, J.J. and Chelsky, D., Biological screening of a large combinatorial library. J. Biomol. Screening, 1 (1996) 27–31. (b) Appell, K.C., Chung, T.D.Y., Solly, K.J., Chelsky, D., Biological characterization of neurokinin antagonists discovered through screening of a combinatorial library. J. Biomol. Screening, 3 (1998) 19–27. (c) Carroll, C.D. and Orlowski, M., Screening aspartyl proteases with combinatorial libraries. Adv. Exp. Med. Biol., 436 (1998) 375–380. (d) Sigal, N.H. and Chelsky, D., Approaches and technologies for screening large combinatorial libraries. In Comb. Chem. Mol. Diversity Drug Discovery, Gordon, E.M. and Kerwin, J.F. (Eds.), Wiley-Liss, NY, 1998, pp. 181–188.
(a) Carroll, C.D., Patel, H., Johnson, T.O., Guo, T., Orlowski, M., He, Z.-M., Cavallaro, C.L., Guo, J., Oksman, A., Gluzman, I.Y., Connelly, J., Chelsky, D., Goldbert, D.E. and Dolle, R.E., Identification of potent inhibitors of plasmodium falciparum plasmepsin II from an encoded statine combinatorial library. Bioorg. Med. Chem. Lett., 8 (1998) 2315–2320. (b) Carroll, C.D., Johnson, T.O., Tao, Shewei, Lauri, G., Orlowski, M., Gluzman, I.Y., Goldbert, D.E. and Dolle, R.E., Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D. Bioorg. Med. Chem. Lett., 8 (1998) 3203–3206.
(a) Tan, D.S., Foley, M.A., Shair, M.D. and Schreiber S.L., Stereoselective synthesis of over two million compounds having structural features both reminicient of natural products and compatible with minaturized cell-based assays. J. Am. Chem. Soc., 120 (1998) 8565–8566. (b) Kapoor, T.M., Andreotti, A.H. and Schreibert, S.L., Exploring the specificity of two homologous SH3 domains using structure-based, split-pool synthesis and affinity-based selection. J. Am. Chem. Soc., 120 (1998) 23–29. (c) Morken, J.P., Kapoor, T.M., Feng, S., Shirai, F. and Schreiber, S.L., Exploring the leucine-proline binding pocket of the Src SH3 domain using structure-based, split-pool synthesis and affinity-based selection. J. Am. Chem. Soc., 120 (1998) 30–36.
Parity tags are generally employed together with the synthon tag set to maintain the total tag count at an even number for any given set of encoded synthons. The parity tags assist in resolving the occasional tag ambiguity which arises from the GC auto scoring function.
The number of random beads that must be sampled from a given library to give a statistically meaningful result is equivalent to 10x the largest combined synthon set. For an account of the statistical sampling methodology see: Dolle, R.E., Guo, J., O'Brien, L., Jin, Y., Piznik, M., Bowman, K.L., Li, W., Egan, W.J., Cavallaro, C.L., Roughton, A.L., Zhao, Q., Reader, J.C., Orlowski, M., Jacob-Samuel, B. and DiIanni Carroll, C., A statistical-based approach to assessing the fi-delity of combinatorial libraries encoded with electrophoric molecular tags. Development and application of tag decodeassisted single bead LC/MS analysis. J. Combin. Chem., 2 (2000) 716–731.
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Dolle, R.E., Guo, J., Li, W. et al. Analysis of libraries encoded with GC tags: Compound elution, tag decode analysis, and statistical sampling analysis. Mol Divers 5, 35–49 (2000). https://doi.org/10.1023/A:1011393414573
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DOI: https://doi.org/10.1023/A:1011393414573