Combinatorial biology is the generation of large numbers of molecules (usually peptides,
enzymes or other
polypeptides in biology) with non-natural
metabolic pathways. The resulting set of molecules is referred to as a library. Because traditional methods of chemical discovery and selection relied on "natural" pathways (those formed by sources found in the wild and brought into the library), creation of the requisite number of peptides for new
drug discovery was impractical. New drugs needed to be built from specific combinations of
proteins among the trillions of possible combinations. Synthetic avenues for peptide generation became an important venue for drug creation in the 1980s. In 1985, Houghten's most cited paper (cited 650 times, according to
Scopus) published his method for the synthesis of massive numbers of peptides—enough for practical use in pharmacological work—in the
Proceedings of the National Academy of Sciences. This method was referred to as the "tea-bag" method because deprotected peptides are enclosed in mesh bags and dipped quickly into liquid solutions containing activated amino acids (or other organic compounds). The peptide is thus elongated one amino acid at each step, and by careful movement of each teabag, a series of related peptides can be made. By another variation, "split and mix", tens of millions of very diverse peptides can be made, and then assayed by some technique. Very precise deconvolution of the results, or alternatively, marking the peptide beads, can correlate sequence and activity. This allowed "[the capture of] information in a day that you couldn't get in a hundred years before" according to Houghten. Houghten continued his work in combinatorial biology with an article in
Methods, the journals section of
Methods in Enzymology. which is the standard multi-volume references set for biochemical methodology in research. == Awards ==