Libraries compound

In addition to natural product sources, chemical compound libraries are used frequently in the drug discovery process. These libraries can range from small, focused libraries specifically synthesized with a particular target in mind to massive, randomly generated libraries. While there is still the problem of deconvolution of an active library, synthetically generated libraries do have a few advantages over natural product extract mixtures. There are typically equal 

FIGURE 28.7 Steps in natural-product-derived drug discovery. 

Compounds with twro or more of the following characteristics are flagged as likely to have poor oral absorption 

The chemical pool in soeening Ubraties must be enriched. As companies concentrate on similar targets, with sCTeening libraries acquired from the same commercial vendors or prepared in-house with automated synthesis from common building blocks, the novelty and patent problem iUCTeases. Compound novelty is a neglected issue that deserves urgent attention. 

Basically, compounds are either prepared in-house or acquired from third parties  

Handcrafted by medicinal chemists Combinatorial chemistry Automated (parallel) synthesis Natural-product derivatives 

The cost and value of these compounds in the drug discovery and development process are discussed later in the chapter. What is worth remembering is that the compound sources are no more than those outlined above. Chemistry is done by people, by machines programmed by people, or by nature—and that is it. 

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One application of clustering could, for example, be the comparison of compound libraries A training set is chosen which contains members of both libraries. After the structures are coded (cf. Chapter 8), a Kohonen network (cf. Section 9.5.3) is trained and arranges the structures within the Kohonen map in relation to their structural similarity. Thus, the overlap between the two different libraries of compounds can be determined. 

To seat ch for available starting materials, similarity searches, substructure searches, and some classical retrieval methods such as full structure searches, name searches, empirical formula searches, etc., have been integrated into the system. All searches can be applied to a number of catalogs of available fine chemicals (c.g, Fluka 154]. In addition, compound libraries such as in-housc catalogs can easily be integrated. 

Figure 10.3-39 shows an example of a substructure search in a catalog of fine chemicals. The precursor illustrated maybe needed, for instance, as a budding block for a compound library. The substructure search provides the avadable structural manifoldness for this precursor. 

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. 

The challenge in the synthesis of chemical libraries is the vast number of different, potentially drug-like small molecules which is estimated to be as high as 1060. As all of these molecules can never be synthesized and tested, it is essential to define criteria for the composition of libraries spanning the biologically relevant areas of the chemical space most efficiently. An important criterion of a compound library is its chemical diversity, a term describing the similarity or dissimilarity of all library components. Thus, chemical diversity expresses how well a library represents all theoretical possibilities within the chemical property space. A library with low... 

If structural information of the protein target is available, e.g., a crystal structure, in silico screening of huge virtual compound libraries can be conducted by the use of docking simulations. Based on identified primary hits, structural variations of the ligand can be evaluated by computational modeling of the ligand-protein complex. 

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. 

Screening of a compound library to detect compounds that bind to the active site of the protein by correlation spectroscopy. 

In both variants of the approach, i) and ii), the ligands detected in a NMR screen would be subjected to further modifications, and become larger during the design process. The properties of the compound library need to fulfill therefore a number of NMR-specific requirements. The compounds need to be soluble in water, their molecular properties should not exceed half the number that is defined in the Lipinski rules for molecular... 

Screening of compound libraries with medium throughput is only possible if the spectra can be recorded in a short period of time, and if one measurement gives simultaneously a number of answers. In practice, several ligands are usually measured in one protein sample, depending on the problem [5]. Mostly 10-20 ligands are combined to multiplexes, which need to be deconvoluted if a positive answer, as shown in Fig. 1 is obtained. The hits obtained maybe analyzed automatically or by hand through manual inspection of the spectra. 

Colony-stimulating Factors Combinatorial Chemistry Compartment Competitive Antagonists Complement System Complement-type Repeat Complex Disease Compound Libraries Compound Optimization Computational Biology Computerized Tomography COMT... 

Root DE, Flaherty SP, Kelley BP, Stockwell BR. Biological mechanism profiling using an annotated compound library. Chem Biol 2003 10 881-92. 

Cases M, Garcia-Serna R, Hettne K, Weeber M, van der Lei J, Boyer S, Mestres J. Chemical and biological profiling of an annotated compound library directed to the nuclear receptor family. Curr Top Med Chem 2005 5 763-72. 

Anderson AC, Wright DL. The design and docking of virtual compound libraries to structures of drug targets. Curr Comp Aided Drug Des 2005 1 103-27. 

Mitchell, M. C., Spikmans, V., Bessoth, F., Manz, a., de Mello, A., Towards organic synthesis in microfluidic devices multicomponent reactions for the construction of compound libraries, in van den Berg, A., Olthuis, W., Bergveld,... 

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