Chemical space combinatorial libraries

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. 

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. 

Summary and comparison of representative methods to search into large virtual chemical space indexed by combinatorial libraries... 

Combinatorial libraries are often synthesized using simple molecules with only a few synthetic steps, whereas natural products are produced in complex multi-step reactions with complex molecules. Also, the parameter space between natural products and chemical libraries seems to be different Synthesized drugs occupy an intermediate space between natural and chemical libraries, also a hint that the space of the drug libraries should be adjusted. 

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. 

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