Diversity libraries

Diverse libraries can be used for lead finding by screening against several different targets. The selected compounds should cover the biological activity space well. 

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Because of their ease of synthesis and their structural similarity to peptides, many laboratories have used peptoids as the basis for combinatorial drug discovery. Peptoids were among the first non-natural compounds used to establish the basic principles and practical methods of combinatorial discovery [17]. Typically, diverse libraries of relatively short peptoids (< 10 residues) are synthesized by the mix-and-split method and then screened for biological activity. Individual active compounds can then be identified by iterative re-synthesis, sequencing of compounds on individual beads, or indirect deduction by the preparation of positional scanning libraries. 

As only small amounts of the hydrogenation products underwent spontaneous cyclization, the compounds were heated in a sealed vessel under microwave irradiation. Due to the low solubility of the cyclized products at room temperature, they precipitated upon cooling and could be easily collected by filtration. The desired dihydropteridinones were obtained in high purity and could be readily used to generate a more diverse library by subsequent N-alkylation [92],... 

Types of Library Design Strategies and Their Uses 4.3.3.1 Diversity Library... 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

In general, larger libraries, other than those of Pharmacopeia and Houghten, have tended to be in the range of 5000 to 15000 compounds, particularly if the enhre library was purified and stored as individual compounds. The same methods and algorithms as for diverse library design apply here. However, it now becomes possible... 

Figure 3.4 Multistage imine formation and metal complexation produces a diverse library of amine-, salicylaldehyde- and salicylaldimine-zinc complexes.

BioFocus has designed and synthesized a niimber of ion channel libraries according to the Theme directed design principles described previously. Initial indications are that these libraries give at least an order of magnitude enhancement in hit rate compared with diverse libraries for channels where hit rates are particularly low more importantly, good selectivity between similar channel subtypes has been regularly observed. 

Fig. 3. Coverage of chemistry space by four overlapping sublibraries. (A) Different diversity libraries cover similar chemistry space but show little overlap. This shows three libraries chosen using different dissimilarity measures to act as different representations of the available chemistry space. The compounds from these libraries are presented in this representation by first calculating the intermolecular similarity of each of the compounds to all of the other compounds using fingerprint descriptors and the Tanimoto similarity index. Principal component analysis was then conducted on the similarity matrix to reduce it to a series of principal components that allow the chemistry space to be presented in three dimensions.

Library design methods can be divided into reactant-based or product-based design. In reactant-based design, reactants are chosen without consideration of the products that will result. For example, diverse subsets of reactants are selected in the hope they will give rise to a diverse library of products. In product-based design, the selection of reactants is determined by analyzing the products that will be produced. 

When molecules are represented by low-dimensional descriptors, then the descriptors can be used to define the axes of a chemistry space. Typical descriptors are a small number of physicochemical properties or the principal components generated by the application of principal components analysis to high-dimensional descriptors. Each descriptor then defines one axis and is divided into a series of bins. The combination of all bins over all descriptors defines a set of cells over a chemistry space. Molecules can be mapped onto the cells according to their physicochemical properties. A diverse library is one that occupies a large number of cells in the space, whereas a focused library is one where the molecules occupy a small localized region of the space. 

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