The use of small molecules has played a key role in biological research, as well as drug discovery (see Section 4.1). Historically, the most important source of small molecules has been nature, which has delivered a wealth of compounds to be applied in both basic research and drug discovery (see Chapter 6). In some cases the natural product could be used directly, but most frequently substantial efforts in medicinal chemistry laboratories were required to optimize the properties of the natural product. In the 1980s and 1990s a chemical discipline emerged, called combinatorial chemistry, which followed the development of high-throughput technologies in biology. Combinatorial chemistry was widely applied in a more systematic search for small molecules, which often were synthesized using solid-phase chemistry. In both academic and industrial settings, combinatorial chemistry was implemented with great hopes for being able to deliver pharmacological tools and drug candidates, faster and more efficiently than, for example, natural products had been able to do. However, it has been realized, that combinatorial chemistry in itself did not succeed in providing better starting points for drug development.
At present there is an urge to find chemistry-based methods and principles that in a most efficient manner can provide pharmacological tools and drug candidates. Besides modern medicinal chemistry and natural products chemistry, that still play pivotal roles in any small-molecule development; novel approaches such as diversity-oriented synthesis (DOS) and fragment-based approaches are currently being investigated, and will be discussed in the following sections. These developments follow developments in related areas to the drug discovery process, such as screening technologies, constitution of compound libraries, systems biology approaches, but a discussion of these areas is beyond the scope of this chapter.
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