Compound collection/library

A chemical library is a precisely defined collection of different chemical compounds. Chemical libraries can be either prepared by parallel synthesis or by split-and-recombine synthesis. 

Centerpieces of combinatorial concepts include the synthesis of compound libraries instead of the preparation of single target compounds. Library synthesis is supplemented by approaches to optimize the diversity of a compound collection (diversity-oriented synthesis) and by efforts to create powerful interfaces between combinatorial synthesis and bioassays. 

A compound library is a compound collection. The compound libraries of large pharmaceutical and screening companies can exceed 1 million samples. Libraries are synthesized and stored as either individual samples or as combinations. 

The previous sections have summarized the basic techniques available for searching chemical databases for specific types of query. Another important database application is compound selection, the ability to select a subset of a database for submission to a biological testing program. The selection procedure can be applied to in-house databases, to externally available compound collections, or to virtual libraries, that is, sets of compounds that could potentially be synthesized. 

The objective of traditional multistep synthesis is the preparation of a single pure compound, but combinatorial synthesis is designed to make many related molecules.57 The purpose is often to have a large collection (library) of compounds for evaluation of biological activity. A goal of combinatorial synthesis is structural diversity, that is, systematic variation in subunits and substituents so as to explore the effect of a range of structural entities. In this section, we consider examples of the application of combinatorial methods to several kinds of compounds. 

The 2005 version introduces spectral duplication 190,825 spectra of 163,198 compounds. The library also now contains a collection of gas chromatographic retention indices for 25,728 compounds on nonpolar chromatographic columns, and a collection of 5191 MS-MS spectra of 1920 ions. The latter multiplicity of MS-MS spectra reflects a dependence of the spectrum on the conditions under which it is recorded. 

Fig. 4.1 Virtual screening tools can be categorized by the compound data to be screened (compound collection, combinatorial library, chemistry space) and the query type (structure-based, ligand-based, descriptor-based, pharmacophore-based). The output is always a list of compounds together with a score quantifying the fit to the query.

As the nature of chemistry space depends upon the way in which compounds are represented, an absolute or universal chemistry space does not exist. Thus, any procedure that utilizes chemistry space may be subject to considerable uncertainty, and the results obtained in different chemistry spaces are likely to differ, sometimes in quite significant ways. This rather daunting circumstance has necessitated the use of practical, heuristic approaches that, while imperfect, have nevertheless performed in a reasonably satisfactory manner over the last three years. During this period about 120000 diverse, quality compounds have been added to our corporate compound collection. This does not include the many compounds obtained from combinatorially derived libraries and special target-directed (e.g., kinase) libraries. 

In generating leads from HTS of corporate compound collections and from focused libraries, there are clearly multiple tools and strategies this situation likely reflects... 

Fig. 10.6 Concept of multitarget affinity specificity screening (MASS). Macromolecular targets (typically structured RNA constructs or proteins) in nondenaturing buffers are mixed in solution with a collection of potential ligands derived from natural product fractions, combinatorial libraries, or other diverse compound collections. The...

One approach to screening subsets of available compounds is to screen sets of compounds that, although not representative of the molecular diversity of the available compound collection, do contain as much structure activity relationship information as possible. An example of this was the Informer Library strategy proposed by CombiChem (which was eventually purchased by DuPont Pharmaceuticals in 1999) (23). Unfortunately, there have been no published applications of this screening strategy that assess its success or failure. 

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