Combinatorial libraries comparisons

Figure 6. Combinatorial libraries comparison cumulative number of molecules selected versus the rank of the spread design for each of 10 random orderings of molecules within (a) Library A (b) Library B.

Wilson-Lingardso, L., Davis, P.W., Ecker, D.J., Hebert, N., Acevedo, O., Sprankle, K., Brennan, T., Schwarcz, L., Freier, S.M., and Wyatt, J.R., Deconvolution of combinatorial libraries for drug discovery experimental comparison of pooling strategies, J. Med. Chem., 1996, 39, 2720-2726. 

Pickett, S.D., Luttmann, C., Guerin, V., Laoui, a., and JAMES, E. DIVSEL and COM PEI B - strategies for the design and comparison of combinatorial libraries using pharmacophoric descriptors. 

The age of ultralarge (50000-150000 member) nonpeptide combinatorial libraries [41, 42, 18] is typified by some of the efforts of Merck [43, 44], Pharmacopeia [45], and Houghten Pharmaceuticals [18, 19, 46-48] during the mid-to-late 1990s. While design details often remain unpublished, diversity analyses of several libraries with qualitative comparison to their biological activity exist in the literature [49, 50]. During this era. 

The concepts of molecular similarity (1-3) and molecular diversity (4,5) play important roles in modern approaches to computer-aided molecular design. Molecular similarity provides the simplest, and most widely used, method for virtual screening and underlies the use of clustering methods on chemical databases. Molecular diversity analysis provides a range of tools for exploring the extent to which a set of molecules spans structural space, and underlies many approaches to compound selection and to the design of combinatorial libraries. Many different similarity and diversity methods have been described in the literature, and new methods continue to appear. This raises the question of how one can compare different methods, so as to identify the most appropriate method(s) for some particular application this chapter provides an overview of the ways in which this can be carried out, illustrating such comparisons by,... 

Stahura, F. L., Xue, L., Godden, J. W., Bajorath, J. (1999) Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases. /Mol Graph Model 17, 1-9, 51-52. 

Summary and comparison of representative methods to search into large virtual chemical space indexed by combinatorial libraries... 

Figure 6.19 Comparison of the (a) measured and (b) predicted mass spectra of a 280 component mixture of combinatorial library C-000,228. (Reprinted with permission from Yates et al., 2001. Copyright 2001 American Chemical Society.)...

Comparison of the perturbed library with that generated in the absence of the trap should indicate which members of the library are interacting with the trap, which effectively offers in situ screening of the combinatorial library. 

Fig. 1. A flow chart comparison of the use of combinatorial libraries and the evolutionary process (see text).

Boger DL, Lee JK, Goldberg J, Jin Q, Two comparisons of the performance of positional scanning and deletion synthesis for the identification of active constituents in mixture combinatorial libraries, J. Org. Chem., 65 1467-1474, 2000. 

Konings DAM, Wyatt JR, Ecker DJ, Freier SM, Deconvolution of combinatorial libraries for drug discovery theoretical comparison of pooling strategies, J. Med. Chem., 39 2710-2719, 1996. 

When used for relative similarity and diversity, only potential pharmacophores that contain the defined special centre-type are used. The frame of reference for similarity/diversity studies is thus changed to one that is focused on the feature of interest distances are now measured relative to this special centre. For example, the special centre could be the centroid of a substructure [10] such as biphenyl tetrazole or diphenylmethane, enabling the calculation and comparison of all 3D pharmacophoric shapes that contain this substructure the substructure is said to be privileged . For structure-based design, the potential pharmacophores in a site can be restricted to those that contain a specific site point (e.g. in a pocket, or at the entrance to a pocket). In the context of combinatorial library design, the relative measure can be those pharmacophoric shapes that contain a special site-point that represents where the attachment point for a reagent would be. In figure 1, the special point would be centre-type number 3, which can be reserved for this purpose. 

The practical limitation on library oversampling depends on screening instrumentation, for which flow cytometry must be considered the gold standard. Commercially available flow cytometers analyze multicolor fluorescence signals and sort desired cells within user-defined gates at a rate of 50,000 cells per second [44], A salient comparison would be to microplate-based robotic screening. Considering each cell in a combinatorial library to be functionally equivalent to a microplate well, a flow cytometer can screen the equivalent of several million 1536-well microplates per day. 

The comparison is different when dealing with combinatorial libraries ... 

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