Directed combinatorial chemistry Diversity

The DCCA CL concept provides a unifying framework within which the various entities and processes considered above can be brought together in a coherent fashion. It emphasizes that informed diversity is the goal, not diversity by sheer number. It opens the way to the development of instructed, target- or property-directed combinatorial chemistry, i.e., of smart combinatorial chemistry, where the sought-after property does the driving ... 

Advances in chemical synthesis have enabled considerable sophistication in the construction of diverse compound libraries to probe protein function [61, 62). However, few general techniques exist that can directly assess binding mechanisms and evaluate ligand afEnities in a multiplexed format. To realize the full potential of combinatorial chemistry in the drug discovery process, generic and efficient tools must be applied that combine mixture-based techniques to characterize protein-ligand interactions with the strengths of diversity-oriented chemical synthesis. 

The recent emergence of combinatorial libraries made up of millions of chemically diverse compounds has revolutionized the drug discovery process. In contrast to the expectations of rational drug design, which enables compounds to be designed based on a detailed understanding of molecular interactions, chemical library diversity allows both direct de novo discovery of lead compounds, as well as enhancement of the activity of existing compounds. Combinatorial chemistry has proven to be a... 

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 poor discovery rate for new leads from combinatorial chemistry approaches indicate that natural products chemistry will continue to warrant support. However attention to source material, particularly the true biological origin of desired metabolites, direct assessments of chemical diversity and effective dereplication strategies, is essential. 

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