Chemical Biology - Drug Design and Discovery - page 60

characterized by encompassing a very broad range of both chemical and biological approaches, it
can generally be classii ed into two main classes of research:
1. Applying small molecules to perturb biomacromolecules
2. Modifying biomacromolecules by chemical methods, and employing such molecules to
probe biological activity
The application of small molecules in biological studies started with the isolation of individ-
ual natural products, and is one of the cornerstones of traditional medicinal chemistry. In the
chemical biology context the application of small molecules is called chemical genetics, where
small molecules are used in a systematic manner to probe biology. Although there is no strict
dei nition of a small molecule, it is generally a small organic molecule, with a molecular weight
between 300 and 700 Da and it is not a biomacromolecule. The modii cation of biomacromol-
ecules (proteins, nucleic acids, and polysaccharides) has emerged as a result of primarily two
things: the understanding of biological systems is reaching a level, where much more detailed
studies are required and at the same time a range of chemically inspired techniques have devel-
oped to modify and study biomacromolecules, which in some cases has surpassed traditional
genetic methodologies.
4.2 SMALL MOLECULES
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 substan-
tial 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 chem-
istry, 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 efi ciently 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 i nd chemistry-based methods and principles that in a most efi cient
manner can provide pharmacological tools and drug candidates. Besides modern medicinal chemis-
try 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.
4.2.1 G ENERATION OF S MALL -M OLECULE P ROBES
Small molecules are at the center of chemical biology and some methods are mentioned for gen-
eration of small molecule that can be applied as probes in studies of biology (Figure 4.1). In recent
years a number of new technologies for identifying such probes have emerged, and in the following
sections two such technologies will be discussed in more detail.