Combinatorial chemistry basic principles

Chapters 1 and 2 have been reorganised and updated in line with recent developments. A new chapter on the Future of Purification has been added. It outlines developments in syntheses on solid supports, combinatorial chemistry as well as the use of ionic liquids for chemical reactions and reactions in fluorous media. These technologies are becoming increasingly useful and popular so much so that many future commercially available substances will most probably be prepared using these procedures. Consequently, a knowledge of their basic principles will be helpful in many purification methods of the future. 

Outline the basic principle underlying combinatorial chemistry. What criteria should be satisfied by the building blocks used in a combinatorial synthesis ... 

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 basic principle of combinatorial chemistry is to prepare a large number of different compounds at the same time - instead of synthesizing compounds in a conventional one-at-a-time manner - and then to identify the most promising compound for further development by high-throughput screening. 

This bead-based procedure is a derivative of the solid-phase chemistry that has proven its merits in automated peptide synthesis [74], combinatorial chemistry [75] and also small-molecule synthesis [76]. The basic principle behind solid-phase synthesis is the attachment of a substrate to a polymer bead by a covalent linker and subsequently performing a chemical reaction on the substrate. Because the substrate is tightly bound to the polymer, excess reagents and by-products can simply be washed away, after which further chemical elaboration of the product may be performed. Finally, the dean product is deaved from the polymeric support, which usually can be regenerated for re-use. 

In Chapter 6 we describe the basic principles of supervised statistical learning and show how it can be used in computer chemistry when a causal connection between structure and property is not known, or can only be calculated with extremely high effort. Such problems occm quite often in combinatorial chemistry as well as in molecular structure elucidation. 

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