Combinatorial library screening 27/8/02. By Richard Twyman Combinatorial libraries are large collections of chemical compounds that are screened to identify potential new drugs.

Most pharmaceutical companies use combinatorial chemistry to create libraries of organic molecules for drug screening (finding candidate molecules, or lead compounds, that interact with a given target receptor in the body) and lead optimisation (perfecting a potentially useful lead molecule).

Essentially, the process involves taking a small number of starting compounds and reacting these with a larger number of reagents. For example, with 20 starting compounds and 50 reagents, 1000 products can be generated. These products can be reacted with a further collection of 50 reagents. The result would be 50 000 second generation products, all based on the 20 starting compounds which would be known as 'skeletons'.

There are two major approaches in combinatorial chemistry. The 'pool and split method' involves attaching the starting compounds to polymer beads. The beads are then split into 50 groups and reacted with the second set of reagents. After this reaction, all the beads are pooled, mixed together, and split into 50 groups again. If mixing is efficient, each group should contain approximately equal numbers of beads representing each of the 1000 first-generation products.

The groups of beads are then reacted with the next set of reagents. If the beads are tagged in some way after each reaction (for example, with a different fluorescent label to identify each reagent) the combination of tags will characterise each of the 50 000 second-generation products exactly. The finished beads can be screened for their ability to bind a particular target protein in the body. The compound with the best performance can be identified and tested further. Additional rounds of pooling and splitting allow libraries with millions of compounds to be generated and subjected to high-throughput screening (HTS).

The second method is called 'parallel synthesis'. All the different chemical structure combinations are prepared separately, in parallel, using thousands of reaction vessels and a robot programmed to add the appropriate reagents to each one. This method is unsuitable for the creation of very diverse libraries but is very useful for the development of smaller and more specialised libraries based on a particular skeleton.