Chemistry Thousands of Candidate Drugs in a Few Easy Steps

Combinatorial Chemistry Thousands of Candidate Drugs in a Few Easy Steps 

There are many different ways to search for new and effective pharmaceuticals. Typically a lead compound is found in nature following extraction (e.g., from tree bark or bacteria) and purification. A library of related compounds may then be created one-by-one through chemical modification of the lead compound, careful purification, and testing. 

Study of the mechanism of action, QSAR, and molecular modeling (see chapter 8) are all systematic methods for design of individual promising candidates followed by laborious synthesis, purification, and testing. 

As so often happens in science, there is some debate about the primacy of the discovery of combinatorial chemistry. After all, it is almost certain that Carl Wilhelm Scheele was the first to discover oxygen (ca. 1771-72) but the discovery was made independently in 1774 by Joseph Priestley who published first. Similarly, Arpad Furka (1931- ), at the Eotvos Lorand University in Budapest, first described the concept that would later be called combinatorial chemistry in a document notarized in May 1982. A Ph.D. thesis by his smdent on this topic was completed in 1987 and presented at conferences in Prague and Budapest in 1988 (a year before the fall of the Berlin Wall and the end of the cold war). His work first appeared in a refereed journal in 1991. In 1984, H. Mario Geysen (1944— ) at Glaxo Wellcome in North Carolina published research that employed combinatorial chemistry. In that year, Richard A. Houghton (1946- ) started the nonprofit Torrey Pines Institute for Molecular Studies and developed the tea bag method of combinatorial chemistry. 

What is clear is that all of these early combinatorial experiments had their basis in the solid-phase peptide synthesis developed in 1964 by Bruce Merrifield (see chapter 7). The Furka split-mix technique is outlined in the figure on page 337. For the sake of brevity, only 3 different components (X, Y, and Z) are depicted and only trimers (3 steps) are depicted so that the library has 3 entries (combinations). In practice, Furka was initially interested in peptide synthesis. If all 20 common amino acids are employed to make a library of pentapeptides, then the number of entries is 20 or 3.2 million. For a decapeptide, the library would have 1.02 x 10 entries. The use of solid-phase beads serves two purposes  

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