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The body fights disease by generating antibodies that bind to invading organisms. The body can make different antibodies by shuffling and reshuffling their constituent parts, but it can't make a special antibody each time it is faced with a new pathogen. So it uses only the antibodies that will work best and makes more of them.
In the past few years, chemists have begun to follow this method to develop new drugs. Instead of looking for signs of a desired activity and then making modifications to the structure, they generate a large number of related compounds and then screen the collection for the ones that could have medicinal value in a process called combinatorial chemistry. Combinatorial chemistry can thus offer drug candidates that are ready for clinical testing faster and at a lower cost than before.
Chemists make collections, or libraries, of screenable compounds by using standard chemical reactions to assemble selected sets of building blocks into a huge variety of larger structures. The techniques of combinatorial chemistry allow them to easily make all the possible combinations.
There are two different combinatorial techniques used. The first, called parallel synthesis, involves assembling all the products separately in their own reaction vessels. This is done by using a microtitre plate that contains tiny wells in which the reactions will occur. A combinatorial synthesis is usually started by attaching the first set of building blocks to inert, microscopic beads made of polystyrene. After each reaction any unreacted material is washed away, leaving only the desired products, which are still attached to the beads. Although the chemical reactions needed to link compounds to the beads and detach them are difficult, the ease of purification can outweigh the problems. Robots can help with parallel synthesis and make the process more accurate and less tedious.
The second technique for generating a combinatorial library is known as a split-and-mix synthesis. It is similar to parallel synthesis but instead of each compound having its own container, a mixture of related compounds are produced in the same container. This method reduces the number of containers required and raises the number of compounds that can be made into the millions, but it makes organizing and the testing the compounds quite complicated, and for this reason, most companies continue to use parallel synthesis.
Both the parallel and the split-and-mix techniques were first used to make peptides. But later chemists learned to make important drug-like compounds, such as benzodiazepines, using these methods. Researchers have also applied the combinatorial techniques to a wide array of starting materials. In general, chemists use combinatorial libraries of small organic molecules as
sources of promising lead compounds or to optimize the activity of a known lead. When searching for a new lead structure, researchers often generate large libraries, in contrast, a library designed only to improve the potency and safety of an existing compound is usually much smaller.
The future of combinatorial chemistry is promising. Many companies, using combinatorial chemistry, have discovered compounds that can be used as drugs. Combinatorial libraries will be generated cheaper and faster. Reaction methods will be found to enhance the final yield of products or replace the need for adding and later removing polystyrene beads. There will also be changes in the way that information about the activity of tested compounds is gathered and analyzed. For example, information on how thousands of compounds in one combinatorial library bind to a particular receptor whose exact structure is unknown can be used to predict the shape, size and electronic charge properties of that receptor. This information can help chemists modify existing leads or choose starting materials for constructing new combinatorial libraries.
Even though combinatorial chemistry seems random and directly opposite of the normal approach involving knowledge and careful prediction, it really isn't. The development of a good combinatorial library involves extensive research, development and planning. Chemists must decide what building blocks to combine, and they must determine how to test the resulting structures for biological activity.
Besides its use for making drugs, combinatorial chemistry can be used in other fields well. It is being used in the science of Superconductivity to identify high-temperature superconductors. Combinatorial techniques have also been applied to liquid crystals for flat-panel displays and materials for constructing thin-film batteries. Scientists working on these
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