Diversity, combinatorial libraries chemical space

Once the initial diversity fetish had run its course and management realized that it was inefficient to attempt to span the entirety of chemical space in search of drugs, more rational approaches based on chemoinformatics were developed to design combinatorial libraries and select candidates for screening on the basis of properties that have proven to be associated with successful therapeutics in the past. 

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,... 

Since diversity is a collective property, its precise quantification requires a mathematical description of the distribution of the molecular collection in a chemical space. When a set of molecules are considered to be more diverse than another, the molecules in this set cover more chemical space and/or the molecules distribute more evenly in chemical space. Historically, diversity analysis is closely linked to compound selection and combinatorial library design. In reality, library design is also a selection process, selecting compounds from a virtual library before synthesis. There are three main categories of selection procedures for building a diverse set of compounds cluster-based selection, partition-based selection, and dissimilarity-based selection. 

The current chemical space is occupied by compounds isolated from nature, synthesised by conventional solution phase synthesis, solid phase combinatorial synthesis and by smaller fragment based libraries. These libraries vary significantly both in their size and complexity. The comparison of diversity of these libraries and their impact as drug leads is reviewed in this chapter. 

The success of both target-based and phenotype-based methods relies heavily on the qualities of the chemical libraries used. Although combinatorial technologies allow the synthesis of a large number of molecules with immense structural diversity, it is impossible to saturate the chemical space, which has been estimated to contain more than 10 molecules (8). Because biological space interacts with only a fraction of chemical space, synthetic attempts to increase randomly the molecular... 

Diversity The unrelatcdncss" of a set of. for example, building blocks or numbers of a combinatorial library. Measured using physicochemical or structural descriptors, a. set with high diversity. spans a larger fraction of "chemical space." Cluster analysis is one technique used to quantify diversity. 

The DOFLA has advantage in the following aspects (Table 17.1). This approach benefits from the combinatorial chemistry techniques, once an efficient synthetic route can be developed for a diverse set of dyes. Thus broader chemical space could be explored and unknown/unexpected molecular interactions might be discovered. The design and preparation of the fluorescent dye library is unbiased to any specific target analyte, and the library would be evaluated with quite distinct analytes to maximize the chance of application in different fields. Taken all these together,... 

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