Compound selection virtual libraries

Scaffold proposals were collected and reviewed according to privileged ion channel motifs, chemical feasibility, and fit to our multiple pharmacophores. Building block selection, virtual library design, and filtering yielded small virtual libraries suitable for automated solution-phase synthesis. All synthesized compounds were finally purified and characterized prior to addition to our focused library. 

The previous sections have summarized the basic techniques available for searching chemical databases for specific types of query. Another important database application is compound selection, the ability to select a subset of a database for submission to a biological testing program. The selection procedure can be applied to in-house databases, to externally available compound collections, or to virtual libraries, that is, sets of compounds that could potentially be synthesized. 

The next vague of tools will be around computational or in silico ADME approaches. These will allow to include ADME into the design of combinatorial libraries, the evaluation of virtual libraries, as well as in selecting the most promising compounds to go through a battery of in vitro screens, possibly even replacing some of these experimental screens. Several of these computational tools are currently under development as will be discussed in this volume. 

The nature of combinatorial chemistry can present a considerable challenge because these libraries are generally produced as arrays of compounds and it is often inconvenient to synthesize individual compounds in order to achieve an optimal design. Two methods have been described that attempt to select optimal subset of reagents from a virtual library that has been partitioned into favorable and unfavorable compounds by some method of filtering. The PLUMS algorithm [97] was designed to simultaneously optimize the size of the library based on effectiveness and efEciency . 

In the early stages of the project when leads do not exist, computational methods can be used to select a diverse set of compounds from a large virtual library. If a compound shows activity then other similar compounds from the library are synthesised and tested. If a lead already exists at the start of the programme, the size of the virtual library can be reduced by selecting a subset of compounds that are similar to the lead. 

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,... 

Enumeration is the computational equivalent of carrying out a combinatorial synthesis. The result is a virtual library of product molecules that can then be analyzed using a library design program to select compounds of interest. Two different approaches to library enumeration have been developed fragment marking and the reaction-transform approach (14). 

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. 

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