Deconvolution orthogonal

The full-scan mode is needed to achieve completely the full potential of fast GC/MS. Software programs, such as the automated mass deconvolution and identification system (AMDIS), have been developed to utilize the orthogonal nature of GC and MS separations to provide automatically chromatographic peaks with background-subtracted mass spectra despite an incomplete separation of a complex mixture. Such programs in combination with fast MS data acquisition rates have led to very fast GC/MS analyses. 

Although not identical, both the orthogonal and positional scan formatted libraries share the features that all mixtures are made at the start of the library process and only individual compound synthesis is required after the first screening of mixtures. This is an extra initial effort with regard to the synthesis of mixtures when compared to an iterative method. The advantage is that no intermediate mixture syntheses will be required. If prepared in sufficient quantity, the library can be screened over a large number of assays, and the added effort of initial mixture syntheses will be translated into an efficiency in deconvolution relative to the continual resynthesis of mixtures with iterative deconvolution. 

Fig. 4. Orthogonal partition combinatorial library approach (A) synthetic scheme of 125 orthogonal sublibraries, AAA, (the same scheme is used for the synthesis of sublibraries BnBnBn) (B) building block partition matrix (C) examples of deconvolution.

Any chemically encoded library requires a double orthogonal chemical strategy, or the construction of elaborate tags/linkers on the solid support prior to the synthesis. Even when these are easily prepared and inert, the synthetic scheme becomes more complicated than direct deconvolution methods, where only the library synthesis is required. Sometimes the tag chemistry and the... 

Several other deconvolution methods have been reported. Orthogonal libraries (168), subtractive deconvolution (169), omission libraries (170), bogus coin deconvolution (171), deletion synthesis deconvolution (172), and mutational SURF (Synthetic... 

The deconvolution of orthogonal libraries is based on the fact that each peptide of the library is present in one sublibrary of A and one sublibrary of B, and that particular peptide is the only one these two sublibraries have in common (see Section 4.3.V.3.2.3). Consequently, after having determined the most-active sublibraries in both libraries A and B in a given bioassay, individual active peptides are identified by deciphering the peptide that the active sublibraries of A and B have in common. If more than one sublibrary is active in each library, many individual peptides representing the common peptides of the different sublibrary pairs from both libraries have to be synthesized and tested in order to identify the... 

Figure 3.24 Deconvolution of the same symmetry components of the motion analysis displayed in Figure 3.34 into orthogonal combinations of the local vectors which distinguish pure vibrations from pure translations.

The synthetic advantages of preparing mixtures instead of individual compounds are offset by the need to deconvolute mixture libraries following bioassay. Deconvolution shortcuts, such as synthesis of multiple libraries containing orthogonal pools (36), are sometimes useful but can only be relied on when the activity of the mixture results from a single highly active compound. Keep-... 

Combinatorial synthesis towards libraries of compound mixtures can be done either on a solid support or in solution. In both cases an effective decoding strategy is required to extract structural information from the results of the biological assay (see Section 1.4.2.1.2 Deconvolution by Orthogonal Libraries). 

Three deconvolution strategies can be used for the structural determination of the biologically most active compounds in a combinatorial library comprising mixtures of up to several thousand compounds (1) iterative deconvolution [47, 98] (2) deconvolution by positional scanning [99-101] or (3) deconvolution by orthogonal libraries [102-104]. 

From the point of view of synthetic effort, preparation of combinatorial mixtures is by far the most economical approach. It can be done with ordinary laboratory equipment and does not take more time than the synthesis of any one of the individual components of the library. This simplicity, however, has its price firstly, the more components a mixture contains the more difficult it becomes to follow the reaction analytically and to determine the actual composition of the reaction product. Secondly, if hits are found in a biological assay, deconvolution is required. In most cases this is done via resynthesis either of the individual components or of subsets of the mixture. If the composition of the initial mixtures was carefully planned it may be possible to identify the active component(s) by simply comparing the composition of the active mixtures with those of the inactive ones. Corresponding procedures have been reported in the literature (e.g., the techniques of indexed [1,2] and orthogonal [3] chemical libraries have been used in solution-phase synthesis). However, the biological effect of a mixture may also be due to a combined action of several weakly active members, with the result that deconvolution does not identify a significantly active compound. Finally, the problem of impurities multiplies with the complexity of the mixtures. 

Grange AH, et al. Determination of ion and neutral loss compositions and deconvolution of product ion mass spectra using an orthogonal acceleration time-of-flight mass spectrometer and an ion correlation program. Rapid Commun Mass Spectrom 2006 20 89-102. 

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