Chemistry, being a highly creative discipline, generates innovative new ideas constantly. Over time, these ideas are incorporated into the corpus of the science, and often subsequently into the technology that drives the chemical enterprise.
Sometimes, though, a new idea has such innovative force that it sweeps through the discipline like a fast-moving brushfire through dry chaparral. Such is the case with combinatorial chemistry, a term that describes a set of tools for generating vast chemical diversity rapidly and efficiently. Combinatorial chemistry has captured the collective imagination of the medicinal chemistry community because of its potential for revolutionizing drug discovery.
Combinatorial chemistry doesn't actually change the drug discovery process, which by necessity involves the screening of large numbers of compounds for potential biological activity. Rather, it introduces a new step, one that greatly increases the range of molecular diversity available to medicinal chemistry. This is done, at least in part, by accepting and harnessing randomness in the synthesis of molecules. The trick is to tame the randomness by creative techniques that allow the medicinal chemist to fish out from a mixture of compounds those that point to drug leads.
The first article in C&EN on a combinatorial approach to chemical synthesis appeared in the Feb. 25, 1991, issue. Nowhere in that article, however, do the terms "combinatorial chemistry" or "combinatorial synthesis" appear.
The term "combinatorial synthesis" appeared in C&EN for the first time in the Jan. 18, 1993, issue in an article describing the work of Jonathan A. Ellman and coworkers at the University of California, Berkeley, on synthesis of a library of 1,4-benzodiazepines. Through 1993, an increasing number of papers on combinatorial approaches to synthesis from an increasing number of independent research groups appeared in the literature, and C&EN's Feb. 7, 1994, cover story was a major wrapup on the field.
As the following three-part Special Report makes clear, the pace of research on combinatorial chemistry, as well as its development as a business in its own right, has continued to quicken over the past two years. Medicinal chemists have made major strides toward improving the synthetic strategies used to generate libraries of compounds, particularly the small organic compounds that are the most promising drug candidates. They have also dramatically refined approaches to labeling compounds synthesized combinatorially so that they can be efficiently screened for biological activity and subsequently identified.
The business side of the equation also has evolved. Many of the small entrepreneurial companies that sprang up to exploit combinatorial chemistry have entered into partnerships with major drug firms that desire access to this new technology. The big drug companies have also set up in-house research programs to exploit combinatorial chemistry. Another side of the business equation has also manifested itself as information management and computational chemistry specialists produce software to deal with the huge volume of data combinatorial chemistry generates.
Truly, this fledgling subdiscipline of medicinal chemistry, only a gleam in the eyes of a few entrepreneurs and academic researchers five years ago, has caught fire.
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