Libraries, chemical

ACD = Available Chemicals Directory CAS = Chemical Abstracts Service CSD = Cambridge Structural Database DEC = dynamically expanding context FA = factor analysis LVQ = learning vector quantization MDS = multidimensional scaling NNT = nearest-neighbor table PCA = principal component analysis QSAR = quantitative structure-activity relationships SOM = self-organized map. 

The study of molecular diversity is a new and incompletely understood field. It is closely related to molecular similarity, structure-activity correlation, and statistical series design, which are thoroughly reviewed in numerous texts. This article records our current awareness, and outlines the most important advances in terms of theory, methodology, and practice. It is divided into four sections that address issues related to molecular representation, dimensionality reduction, quantification and subset selection, and visualization. The reader is also referred to excellent reviews by Martin et al., Blaney et al., and Martin et al.  

The first attempts to quantify molecular diversity focused on physicochemical properties as a means of defining the diversity space. These properties can be calculated using standard molecular modeling and quantum mechanical packages, and include the dipole moment, HOMO and LUMO energies, heat of formation, total energy, ionization potential, number of filled 

Substructure keys encode molecular information in the form of binary arrays or bitmaps (see Substructure Searching). Each element (or bit) in the array can take the values true or false , and indicates the presence or absence of a specific structural feature or pattern in the target molecule. Substructure keys were originally designed for large-scale database searching, but have also proven effective in similarity applications. 

To define a structural key, one defines the structural features of interest, assigns a bit to each one of these features, and generates the bitmap for each compound in the database. Typical features include the presence, absence, or minimum number of occurrences of a particular element (e.g, the presence of at least one, two, or three nitrogen atoms), unusual 

Some Principles Related to Chemogenomics in Compound Library and Template Design for CPCRs 

Recently, new comprehensive approaches have been developed that use compound libraries for screens in whole living cells using specific phenotype readouts. Some of the applications of this type of approach have been called chemical genetics or chemogenomics [9-27]. In many instances it is probably more accurate to call 

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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]. 

W Zheng, SI Cho, A Tropsha. Rational combinatorial library design 1. Focus-2D A new approach to the design of targeted combinatorial chemical libraries. J Chem Inf Comput Sci 38 251-258, 1998. 

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24... 

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. 

Combinatorial Chemistry. Figure 1 Whereas in classical chemical synthesis one target molecule was prepared in combinatorial chemistry the systematic combination of building blocks generates chemical libraries. 

Precisely defined collections of different chemical compounds are denominated as chemical libraries that can be efficiently prepared by methods of combinatorial chemistry. Each chemical compound owes specific structural, steiic, and electronic properties that determine all possible interactions of the small molecule with a given protein or receptor. The molecule s properties are based on the steiic arrangement of functional groups, including the conformations that can be attained by a specific structure. 

Complex optimization of the ligand-protein interactions require to scan large areas of the chemical space. Thus, the combinatorial chemist aims not at the preparation of single compounds but of chemical libraries. Chemical libraries can be produced as collections of single compounds or as defined mixtures. 

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... 

Combinatorial Chemistry. Figure 2 Chemical libraries are prepared either by parallel synthesis or by the split-and-recombine method. In the latter case, coupling m building blocks in m separated reaction flasks through n synthetic cycles on a beaded polymer carrier generates a combinatorial library with nf individual compounds and one compound per bead. 

Components of the JAK-STAT signaling pathway represent novel targets for pharmacological interventions [4]. Recently, a specific and orally active JAK3 antagonist was identified from screening of a chemical library for inhibitors of in vitro JAK3 kinase activity. The most effective compound, CP-690,550, was shown... 

Cheese Reaction Chemical Chaperone Chemical Library Chemical Neurotransmission Chemoattractant Receptors Chemokine Receptors Chemokines... 

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). 

The practical utility of the target-structure-based approach in the design of chemical libraries is still limited because of the requirement of quality crystallographic data, detailed knowledge of the ligand binding mode, and... 

Poor pharmacokinetics and toxicity are important causes of costly late-stage failures in drug development. It is generally recognized that, in addition to optimized potency and specificity, chemical libraries should also possess favorable ADME/Tox and druglike properties [77-80]. Assessment of druglike character is an attempt to decipher molecular features that are likely to lead to a successful in vivo and, ultimately, clinical candidate [81-83]. Many of these properties can be predicted before molecules are synthesized, purchased, or even tested in order to improve overall lead and library quality. 

Knowledge-based data mining algorithms used for correlation of molecular properties with specific activities play an increasingly significant role in modern strategies of chemical library design as relatively inexpensive, yet comprehensive tools. The ability to identify compounds with the desired... 

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. 

Savchuk NP, Balakin KV, Tkachenko SE. Exploring the chemogenomic knowledge space with annotated chemical libraries. Curr Opin Chem Biol 2004 8 412-17. 

Savchuk NP, Balakin KV. Data mining approaches for enhancement of knowledge-based content of de novo chemical libraries. In Alvarez H, Shoichet B, editors, Virtual screening in drug discovery. New York CRC Press, 2005. p. 121-49. 

Shoichet BK. Virtual screening of chemical libraries. Nature 2004 432 862-5. 

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

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