Diversity, combinatorial libraries definition

This paper reviews recent advances on computational aspects of molecular diversity, with particular emphasis on methodology and applications. There are probably as many different definitions of diversity as the number of researchers who are active in the field, and it is our belief that theoretically the subject borders on religion. However, many of the concepts described herein are now routinely employed in combinatorial library design, and the choice of methods has definitive and measurable practical implications. The article is divided into three main sections that address issues... 

Partitioning or cell-based methods are based on the definition of a low-dimensional property space. The range of values for each property is divided into a set of bins and the combinatorial product of all bins then defines the set of cells that make up the space. Each molecule in a library is assigned to a cell according to its physical properties. A diverse subset of compounds can be selected by taking one or more molecules from each cell, whereas a focused set of compounds can be selected by choosing compounds from a limited number of cells, for example from those cells that surround the cell occupied by a known active compound. 

This chapter has reviewed the basic principles of computer-aided drug design, and several strategies of how it can be successfully integrated with combinatorial chemistry to develop highly effective site-focused libraries. Diversity plays a key role, as the more diverse set of compounds tested that fit the site-focused criteria, the more information is retrieved to improve the site-focused definition, which further directs the search in diversity space. In addition, if good hits are found, the information can be fed back to find compounds close in diverse space to the hit. This new paradigm for structure-based combinatorial chemistry should provide a powerful tool for rapid discovery of novel, potent lead compounds in the years to come. 

The design strategies employed to improve combinatorial chemistry have evolved considerably since the early days of peptide and peptidomimetic libraries. The main concern early was on the availability of suitable synthetic methods that could be applied to the synthesis of libraries of small molecules however, this early obstacle has been intensively addressed and at this point can be considered overcome (for examples of new methodology developed for library production see Ref 21). With the ability in hand to prepare many different types of molecules in a variety of formats, the current challenge is to decide what compounds to make. As a consequence, much attention is now focused on the definition and analysis of chemical diversity. 

A broadly accepted definition of HTE or combinatorial catalysis is that it is a methodology or a set of tools where large diversities of solid-state materials libraries are prepared, processed and tested predominantly for activity and selectivity [2]. However, catalysts are not combined and tested as a combination of different catalysts, with the impetus to speed up testing routines by using the combine and split methodology as established in pharmaceutical industry. Catalysts are usually synthesized sequentially or in parallel by means of robots following conventional synthesis recipes. 

Application of the considerations above to polymer chemistry leads to the definition of constitutionally dynamic polymers, dynamers, of both molecular and supramolecular types (Fig. 1) [29-32]. They behave as dynamic combinatorial entities, based on dynamic libraries whose constituents have a combinatorial diversity determined by the number of different monomers. The components incorporated by polyassociation or by polycondensation into the supramolecular or molecular polymer chains depend on the nature of the connections (recognition patterns or functional groups) and core groups, as well as on the interactions with the environment, so that dynamers possess the capacity of adaptation by association/growth/ dissociation sequences. 

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