Empirical biochemistry
Empirical chemistry, coupled with a knowledge of applied pharmacology, has been an important source of new medicines. Iterative modifications of a prototype molecule can lead to important changes in its profile that lead, for example, to improvements in its receptor specificity, or how well it is absorbed. Traditionally, this was a laborious process involving synthesis of a range of related compounds, purification, and repeat testing in a pharmacological model (e.g. an isolated muscle preparation).
The new technique of combinatorial chemistry allows a huge range of related chemical structures to be produced relatively quickly (Fig 2). The key of combinatorial chemistry is that a large range of analogues is synthesised using the same reaction conditions and the same reaction vessels.
The rate-limiting factor is now the development of suitable systems in which to test the compound library. Screening against receptor subtypes is relatively straightforward but complex second messenger systems pose much greater practical challenges.
Combinatorial chemistry
Fig 2 Dynamic combinatorial chemistry is a powerful technique for discovering new ligands for biomolecules such as receptors and enzymes. Molecular 'libraries' are created by linking simple molecules together using a reversible reaction that reaches an equilibrium that contains a mixture of combinations. The amount of each of the library members is directly related to their thermodynamic stability. This means that the mixture is ideal for identifying new compounds that are good at molecular recognition. These that recognise and bind new molecules achieve the greatest stability. This shifts the equilibrium in favour of the best binders at the expense of the poor receptors.
