Mixture-based synthetic combinatorial libraries

The field of combinatorial chemistry has grown exponentially in the past decade. It can be expected that all aspects of combinatorial chemistry will continue to develop as researchers refine these methods and use them to identify relevant compounds in a variety of biological as well as nonbiological systems. Not only have automated high-throughput screening systems greatly improved in recent years, but it is also likely that the daily synthesis of thousands of compounds will seem routine in the very near future. Mixture-based combinatorial library approaches will continue to find favor with researchers who have limited resources, limited knowledge of their biological target, and/or assays that are not amenable to classic highthroughput methods. Mixture-based libraries offer a powerful advantage in that very large diversities can be synthesized and screened in a rapid and cost-efficient manner. Mixtures also enable large numbers of compounds to be tested in 'low-throughput' assays (e.g., tissue and/or in vivo systems) and in those systems in which target reagents are limited by availability or cost. The methods encompassed by combinatorial chemistry are now 15 years old. As with virtually all new and far reaching methods, combinatorial methods have been slow to win acceptance. As discussed in this Perspective, this has been especially true for mixture-based combinatorial methods. The resistance to mixture-based methods is likely due to the distance between these approaches and the traditional 'one at a time' methods the pharmaceutical industry has successfully employed for decades. As with all innovations, only those methods that prove to be practical will eventually be embraced by those who will benefit by their use. What began as a need to produce larger numbers of compounds per unit time (approaches such as Merrifield's solid-phase method and the pin and tea bag parallel methods) has now evolved to permit an individual to synthesize not just hundreds of compounds per year but hundreds of thousands or even millions. Combinatorial methods include high-throughput parallel synthesis, phage display approaches, synthetic mixtures, one-bead-one-compound concepts, etc. These were first directed toward and used by the pharmaceutical industry but have now evolved to encompass all areas of research and development that benefit from increased numbers and/or rapid information gathering. As originally presented and now practiced, combinatorial chemistry results in a tremendous increase in the information gathering capabilities across all areas of scientific exploration. In the future, the concepts inherent in combinatorial approaches will be applied to a wide range of other disciplines and interests. Thus, new materials will be devised, synthetic chemical reactions will be readily optimized, and chemical information gathering will be greatly improved. The de novo design of highly specific receptors, new ceramic materials, and artificial catalytic compounds will also be developed by the application of combinatorial methods to these areas. The future direction of combinatorial methods has such a broad range of possibilities that the most important and greatest impact will likely be in an area that has not yet even been considered. What is clear, however, is that combinatorial methods have forever changed the expectations of chemists, biologists, immunologists, molecular biologists, and their organizations in terms of what can and must be done in a given period of time. While combinatorial methods are now becoming more and more part of the routine tools used by the scientific community, they have forged interdisciplinary collaborations that would have been inconceivable in earlier times and with earlier methods. We believe that combinatorial methods will continue to evolve and be used in other areas of basic research and applied science.