Analysis of combinatorial libraries

Lewis RA, Mason JS, McLay, IM. Similarity measures for rational set selection and analysis of combinatorial libraries The diverse property-derived (DPD) approach. J Chem Inf Comput Sci 1997 37 599-614. 

Gaecia-Egido, E., Spikmans, V., Wong, S. Y. E., Warrington, B. H., Synthesis and analysis of combinatorial libraries performed in an automated micro-reactor system. Lab. Chip 3 (2003) bl-TL. 

Snively, C.M. and Lauterbach, J. (2002) Sampling accessories for the high-throughput analysis of combinatorial libraries using spectral imaging. Spectroscopy, 17, 26. 

Finally, the small sample requirement makes this a suitable method for the analysis of combinatorial libraries. Furthermore, the coupling of a microscope to a motorized stage allows for fully automated analyses [179]. However, the high cost of this instrumentation means that many researchers need to use alternative techniques. 

IR spectroscopy is a fast, simple, and cheap method for the qualitative detection of certain functional groups on insoluble supports [77-79]. Dried supports can be used directly to prepare KBr pellets for standard recording of IR spectra [54,80-82], Newer IR-based techniques, which require much less support material than required for a KBr pellet, include single-bead FT-IR spectroscopy [16,77,83-86], single-bead Raman spectroscopy [87], near-IR multispectral imaging [88], and the simultaneous analysis of several different beads by FT-IR microscopy for analysis of combinatorial libraries [89,90],... 

High-Throughput Parallel LC/UV/MS Analysis of Combinatorial Libraries... 

In LC/MS analysis of combinatorial libraries, the MS determines the product identity and its purity is determined by other on-line detection techniques such as UV, evaporative light scattering detection (ELSD), and chemiluminescent nitrogen detection (CLND).17-20 UV detection is used here to assess product purity based on the assumption of similar absorption coefficients at 214 nm for the desired product and the side-products. 

Nawrocki, J. P., Wigger, M., Watson, C. H., Hayes, T. W., Senko, M. W., Benner, S. A., and Eyler, J. R. (1996). Analysis of combinatorial libraries using electrospray Fourier transform ion cyclotron resonance mass spectrometry. Rapid Commun. Mass Spectrom. 10 1860-1864. 

To avoid bottlenecks in the analysis, each step should be automated. Automation of data acquisition is achieved by automated HPLC/UV/MS/ ELSD instruments, equipped with autosamplers that allow compounds to be batch analyzed in unattended fashion. Recently, fast generic HPLC methods have been implemented for analysis of combinatorial libraries [33 53]. 

Vestal C, Li LYT, Towle MR, Kyranos IN, Evaluation of an automated high throughput LC/MS system for the analysis of combinatorial libraries, Proc. 45th ASMS Conf, p. 1249, 1997. 

LC-NMR data may be acquired in either onflow or stopped-flow modes. In the onflow mode, effluent flows directly from the column through the probe, where spectra are collected at fixed time intervals. Figure 4 shows a typical onflow LC-NMR spectrum.6 In the stopped-flow mode, several fractions are collected and analysed individually at a later time. Although mass spectrometry continues to be the favoured technique for the analysis of combinatorial libraries, the value of LC-NMR was demonstrated in a study by Chin et al.A1 in a stopped-flow study of four positional isomers of dimethoxybenzoylglycine. Iso-molecular-weight mixtures such as this can be problematic to analyse using mass spectrometry however, in this case assignment of the compounds was readily accomplished from the LC-NMR data (Fig. 5). 

An alternative approach for the analysis of combinatorial libraries has been to remove the chromatographic column from the LC-NMR system to generate... 

Lewis, R.A., Mason, J.S. and McLay, I.M. Similarity Measures for Rational Set Selection and Analysis of Combinatorial Libraries The Diverse Property-Derived (DPD) Approach. J. Chem. Inf. Comput. Sci., 1997,37,599-614. 

Perry, N Selection of diverse database subsets by fingerprint and property-based methods. Paper presented at the Chemical Structure Association/Molecular Graphics and Modelling Conference on Computational Approaches to the Design and Analysis of Combinatorial Libraries , University of Sheffield. 14-16 April 1998. 

Coupled chromatography-mass spectrometry techniques for the analysis of combinatorial libraries... 

Recently, LC/UV/MS using atmospheric ionisation sources (API) has become ubiquitous wherever large numbers of samples require automated separation and identification analysis. This is especially the case within the pharmaceutical industi where its universal adoption has coincided with the paradigm shift in the way drug discovery is performed. Today, LC/UV/MS is the front-line technique for the analysis of combinatorial libraries and as an introduction it is useful to examine the development of the technique alongside combinatorial synthesis to understand the synergies that make them good bed fellows . 

Recent years has seen a paradigm shift in the way drugs are discovered and produced. Many areas of drug discovery rely on combinatorial approaches to produce more opportunities and screen more compounds. This has altered the way analysis is performed in all areas and none more so than in the analysis of combinatorial libraries. The rapid development of specialised coupled chromatography-mass spectrometry techniques for... 

J.P. Nawrocki, M. Wigger, C.EI. Watson, T.W. Elayes, M.W. Senko, S.A. Benner, J.R. Eyler, Analysis of combinatorial libraries using ESI-FT-ICR-MS, Rapid Commun. Mass Spectrom., 10 (1996) 1860. 

Leroy, F., Presle, B., Verillon, F. and Verette, E. Fast generic-gradient reversed-phase high-performance liquid chromatography using short narrow-bore columns packed with small nonporous silica particles for the analysis of combinatorial libraries. ]. Chromatogr. Sci. 39 487-490, 2001. 

Sell, C. S. (2008). Rational odorant design Fantasy or feasibility Perfum. Flavor. 33,48-52. Singh, N., Guha, R., Giulianotti, M. A., Pinilla, C., Houghten, R. A., and Medina-Franco, J. L. (2009). Chemoinformatic analysis of combinatorial libraries, drugs, natural products, and molecular libraries small molecule repository. J. Chem. Inf. Model. 49,1010-1024. 

Theoretical and experimental results by Blom (45) have focused on the precision requirements for the mass spectrometric analysis of combinatorial library mixtures. In his work, Blom has used discrete mass filters in combination with mass-MS/MS, M + 1/M, and M + 2/M isotope ratio filters to determine library components specifically from peptide libraries. As pointed out below, while nonpeptide libraries have mass distributions that are completely random, peptide library building blocks are limited in their diversity,... 

Figure 1 Mass spectrometric analysis of combinatorial libraries L1-L6 gray, detected in positive ion ESI black, detected in negative ion ESI vertical stripes, detected in both modes X, detected in MS/MS experiment. (Reprinted from Ref. 30.)...

DC Tutko, KD Henry, BE Winger. Sequential MS and MS analysis of combinatorial libraries by using automated MALDI-FT/MS. Proceedings of the 45th ASMS Conference on Mass Spectrometry and Allied Topics, Palm Springs, CA, 1997, P. 1259. 

A search of the recent literature on the use of HPCE for the analysis of combinatorial libraries shows that as of today not a great deal of work has been done in this area. In fact, only seven published papers could be found, four of which are from the same group (86-88). However, as three of the seven were published in 1996 (88-90), it can be suggested that perhaps this research area is now picking up and will show more results in the near future. 

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