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Development of Combinatorial Chemistry

From a historical perspective, the research efforts made in classical combinatorial chemistry can be briefly outlined in three phases:

In the early 1990s, the initial efforts in the combinatorial chemistry arena were driven by the improvements made in high-throughput screening (HTS) technologies. This led to a demand for access to a large set of compounds for biological screening.

To keep up with this growing demand, chemists were under constant pressure to produce compounds in vast numbers for screening purposes. For practical reasons, the molecules in the first phase were simple peptides (or peptide-like) and lacked the structural complexity commonly found in modern organic synthesis literature.

The second phase started in the late 1990s, when chemists became aware that it is not just about numbers; but something was missing in compounds produced in a combinatorial fashion. Emphasis was thus shifted towards quality rather than quantity.

Like the first phase, the third phase had its origin in progress made by the biomedical community. As the scientific community moved into the post-genomic chemical biology age, there was a growing demand in understanding the role of newly discovered proteins and their interactions with other bio-macromolecules (i.e. other proteins and DNA or RNA). For example, the early goals of the biomedical research community were centered on the identification of small-molecule ligands for biological targets, such as G-protein-coupled receptors (GPCRs) and enzymes.

However, the current challenges are moving in the direction of understanding bio-macromolecular (i.e. protein-protein, protein-DNA/RNA) interactions and how small molecules could be utilized as useful chemical probes in systematic dissection of these interactions. By no means will this be a trivial undertaking! The development of biological assays towards understanding biomacromolecular interactions is equally challenging as the need for having access to useful small molecule chemical probes.

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