Chemical libraries, diversity

The recent emergence of combinatorial libraries made up of millions of chemically diverse compounds has revolutionized the drug discovery process. In contrast to the expectations of rational drug design, which enables compounds to be designed based on a detailed understanding of molecular interactions, chemical library diversity allows both direct de novo discovery of lead compounds, as well as enhancement of the activity of existing compounds. Combinatorial chemistry has proven to be a... 

Chemoinformatics (or cheminformatics) deals with the storage, retrieval, and analysis of chemical and biological data. Specifically, it involves the development and application of software systems for the management of combinatorial chemical projects, rational design of chemical libraries, and analysis of the obtained chemical and biological data. The major research topics of chemoinformatics involve QSAR and diversity analysis. The researchers should address several important issues. First, chemical structures should be characterized by calculable molecular descriptors that provide quantitative representation of chemical structures. Second, special measures should be developed on the basis of these descriptors in order to quantify structural similarities between pairs of molecules. Finally, adequate computational methods should be established for the efficient sampling of the huge combinatorial structural space of chemical libraries. 

Many reports have been published that address various aspects of diversity analysis in the context of chemical library design and database mining [77-84]. 

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... 

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

Agrafiotis D. Diversity of chemical libraries. In Allinger NL, Clark T, Gasteiger J, Kollman PA, Schaefer HP HI, Schreiner PR, editors. Encyclopedia of computational chemistry. Chichester Wiley, 1998. p. 742-61. 

Agrafiotis DK. A constant time algorithm for estimating the diversity of large chemical libraries. / Chem Inf Comput Sci 2001 41 159-67. 

To most effectively search chemical libraries for diverse lead molecules, enzyme assays used for HTS must take into account the conformational dynamics of enzyme catalysis and the physiological context of enzyme action in vivo. 

Applications of the cross-metathesis reaction in more diverse areas of organic chemistry are beginning to appear in the literature. For example, the use of alkene metathesis in solution-phase combinatorial synthesis was recently reported by Boger and co-workers [45]. They assembled a chemical library of 600 compounds 27 (including cisttrans isomers) in which the final reaction was the metathesis of a mixture of 24 oo-alkene carboxamides 26 (prepared from six ami-nodiacetamides, with differing amide groups, each functionalised with four to-alkene carboxylic acids) (Eq.27). 

Chemithon film sulfonating-sulfating systems, 23 544-547 Chemithon reactor, 23 544 Chemoinformatics, 6 1-25 chemical databases, 6 19-20 chemical information retrieval, 6 6—19 chemical information storage, 6 2-6 chemical library design, 6 17-18 clustering techniques, 6 16-17 conformational flexibility, 6 10-11 conformational searches, 6 10-11 data analysis and preparation, 6 20-21 data searching, 6 6-19 diversity searches, 6 14-18... 

Dolle, R., Comprehensive survey of chemical libraries yielding enzyme inhibitors, receptor agonists and antagonists, and other biologically active agents 1992 through 1997, Mol. Diversity, 1998, 3, 199-233. 

Many of the routes reported for the construction of diverse chemical libraries are often constrained by the commercial availabihty of the monomer sets used as the primary building blocks. While there are a large number of simple starting materials currently available, chemists would prefer to have ready access to more sophisticated and highly functionahzed monomer units which would lead rapidly to drug-like molecules. 

Willett, P. Chemoinformatics -similarity and diversity in chemical libraries. Curr. Opin. Struct. Biol. 2000,... 

We will synthesize a chemical library of small molecules with maximal structural diversity and a format compatible with protein binding assays. 

Triciribine, also known as Akt/protein kinase B signaling inhibitor-2 (API-2) compound 52, Fig. 9), was identified by screening the National Cancer Institute Diversity Set chemical library (1992 compounds). The screen was performed using a cell-based proliferation assay with PKB/1 transformed NIH3T3 cells, and triciribine scored positive in this assay with an IC50 value of 50 nM [ 196]. Although the compound blocks the cellular phosphorylation... 

The synthesis of chemical libraries loaded with structural diversity is an emerging field with direct applications in biomedical research. Strategies for library synthesis have mainly focused on combinatorial synthesis of molecules that vary substituents with a core... 

Willett, P. (2000) Chemoinformatics—similarity and diversity in chemical libraries. 

In the context of general screening, computational library design involves the selection of a subset of compounds that are optimally diverse and representative of available classes of compounds, leading to a non-redundant chemical library for biological testing. Methods reported in the literature include... 

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