Diversity Among Libraries

Martin and co-workers counted the total number of substructural fragments up to seven bonds long found in entire libraries as an estimate of chemical functional group diversity. They showed that although synthetic oligomeric combinatorial peptoid libraries were far more diverse than combinatorial biopolymer libraries, they still contained only about as many substructures as just the 45 top selling small molecule drugs. 

Boyd et al. developed the HookSpace Index as a measure of the orientational diversity between pairs of common functional groups in a database of compounds. Analysis of the Cambridge Structural Database of crystallographic structures showed that the HookSpace Index for pairs of functional groups was highly correlated with the number of occurrences of those pairs of groups. 

The Chemical Design Ltd. approach is very attraaive because it uses flexible 3D information. However, it implicitly assumes that the presence of a 

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Johnson, L. K., Brown, M. B., Carruthers, E. A., Ferguson, J. A., Dombek, P. E., and Sadowsky, M. J. (2004). Sample size, library composition, and genotypic diversity among natural populations of Escherichia coli from different animals influence accuracy of determining sources of fecal pollution. Appl. Environ. Microbiol. 70,4478M485. 

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. 

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

In contrast, combinatorial libraries represent a subclassification and define a library in which every possible member that can be generated from the sets of reactants is present. Such libraries can be prepared by parallel synthesis, but are much more commonly synthesized by either mixture synthesis or split synthesis. Because of a commonality in structure among the members in each set of reactants and the optimized reaction conditions used, combinatorial libraries are composed of variants around a scaffold where the substituents control much of the diversity. 

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