Combinatorial chemistry is in this category. Based on the idea of using a solid support laced with reactive sites to which various chemical moieties can be attached one by one, this technique is now one of the basic tools of modern pharmaceutical research. It derived from the research of Professor Bruce Merrifield of the Rockefeller University, initially outlined in his paper published by the American Chemical Society in 1963 (1). He received the 1984 Nobel Prize in Chemistry for this work.

But when the paper was published, who could see the application to today’s pharmaceutical research? Consider this quote from an article in the first issue of the Journal of Combinatorial Chemistry, which appeared in 1999: “[In 1988,] none of us realized the potential of this technique [i.e., combinatorial chemistry] for the development of new drugs; at that time we were ‘entrenched’ in the approach of making one compound at a time, analyzing it, and evaluating it biologically. . . . Even in the 1990s the world was not ready to accept the idea of building libraries of organic molecules and screening them to find interesting compounds” (2).

In fact, if you search on Lexis/Nexis for the term “combinatorial chemistry”, the first instance of its use appears to be in a 1992 paper (3). Now, less than a decade later, to quote Roland Dolle on page 44 of this issue, we have the “first [report] of an efficacious and orally active compound obtained directly from an optimization library.” In that article, Dolle reports that a “500-member optimization library played a defining role in the identification of a clinical candidate.” Clearly, we are beginning to find new drugs faster, better, and presumably cheaper, using combinatorial chemistry.

Of course, it is easy to be oversold on a particular technique, even one with as much promise as this one. In the middle of the last decade, thousands of chemicals were thrown into the combichem process just to see whether one might exhibit some therapeutic response. This was truly the shotgun approach, and it was probably not very efficient. Now, we are using this tool more efficiently. Targeted libraries are more the norm, and with the decoded genes in many databanks, we will likely become more efficient at picking targets and finding candidates. My bet is that combinatorial chemistry, like NMR or LC-MS, will be used in laboratories with carefully selected libraries. It will be a synthesis of the shotgun with a carefully selected library used for a specific target identified from a DNA sequence. Not bad for a technique that didn’t begin to come into its own until the 1990s.

References

1. Merrifield, R. B. Solid-phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 1963, 85, 2149–2154.
2. Lebl, M. Parallel personal comments on “classical” papers in combinatorial chemistry. J. Comb. Chem. 1999, 1 (1), 3–24.
3. Brenner, S.; Lerner, R. A. Encoded combinatorial chemistry. Proc. Natl. Acad. Sci. U.S.A. 1992, 89 (12), 5381–5383.