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Figure 2
Some heuristic rules frequently used in structure-based drug
design. The positions of “bound” water molecules are key
indicators for lead modification sites.
outlined below, both the scaffold modification and structural recombination strategies are key
components of an integrated drug discovery technology that combines structure-based design and
combinatorial chemistry.
III. Combinatorial Chemistry
Page 528
Combinatorial chemical technology enables the parallel synthesis of organic compounds through the
systematic addition of defined chemical components using highly reliable chemical reactions and robotic
instrumentation [8–11]. Large libraries of compounds result from the combination of all possible
reactions that can be done at one site with all the possible reactions that can be done at a second, third,
or greater number of sites. Combinatorial chemical methods can potentially generate tens to hundreds of
millions of new chemical compounds as mixtures, attached to a solid support, or as individual
compounds. The first combinatorial libraries with millions of members were oligopeptide and
oligonucleotide libraries for which reliable and versatile chemical reactions already existed [10,12,13].
However, these libraries were not generally useful as a source of leads for small-molecule
pharmaceuticals due to the relatively high molecular weight of the resulting leads and other limitations
of oligonucleotides and oligopeptides as drugs. More recently, “drug-like” libraries have been produced
that offer much greater utility as a source of drug leads (Figure 3). However, practical limitations of the
versatility and reliability of the chemical reactions used to make these libraries have resulted in
somewhat smaller sets of compounds [14–18].
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