Combinatorial chemistry

Combinatorial chemistry is a technique by which large numbers of structurally distinct molecules may be synthesised in a time and submitted for pharmacological assay. The key of combinatorial chemistry is that a large range of analogues is synthesised using the same reaction conditions, the same reaction vessels. In this way, the chemist can synthesise many hundreds or thousands of compounds in one time instead of preparing only a few by simple methodology.Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials

Synthesis of molecules in a combinatorial fashion can quickly lead to large numbers of molecules. For example, a molecule with three points of diversity (R1, R2, and R3) can generate NR1*NR2*NR3 possible structures, where NR1 ,NR2 , and NR3 are the number of different substituents utilized.

Although combinatorial chemistry has only really been taken up by industry since the 1990s, its roots can be seen as far back as the 1960s when a researcher at Rockefeller University, Bruce Merrifield, started investigating the solid-phase synthesis of peptides. Professor Pieczenik, a colleague of Nobel Laureate Merrifield synthesized the first combinatorial library. In the 1980s researcher H. Mario Geysen developed this technique further, creating arrays of different peptides on separate supports but not a combinatorial library based on random synthesis.

In its modern form, combinatorial chemistry has probably had its biggest impact in the pharmaceutical industry. Researchers attempting to optimize the activity profile of a compound create a 'library' of many different but related compounds. Advances in robotics have led to an industrial approach to combinatorial synthesis, enabling companies to routinely produce over 100,000 new and unique compounds per year.

In order to handle the vast number of structural possibilities, researchers often create a 'virtual library', a computational enumeration of all possible structures of a given pharmacophore with all available reactants. Such a library can consist of thousands to millions of 'virtual' compounds. The researcher will select a subset of the 'virtual library' for actual synthesis, based upon various calculations and criteria.
Combinatorial chemistry is one of the important new methodologies developed by researchers in the pharmaceutical industry to reduce the time and costs associated with producing effective and competitive new drugs.

By accelerating the process of chemical synthesis, this method is having a profound effect on all branches of chemistry, but especially on drug discovery. Through the rapidly evolving technology of combi-chemistry, it is now possible to produce compound libraries to screen for novel bioactivities. This powerful new technology has begun to help pharmaceutical companies to find new drug candidates quickly, save significant money in preclinical development costs and ultimately change their fundamental approach to drug discovery.


Development of Combinatorial Chemistry
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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.