1988

Modern Drug Discovery

George Herbert Hitchings (1905–1998), Gertrude Belle Elion (1918–1999), James Whyte Black (1924–2010)

In 1988, three of the biggest names in the history of medicinal chemistry were awarded the Nobel Prize in Physiology or Medicine “for their discoveries of important principles for drug treatment.” American coworkers Gertrude Belle Elion and George Herbert Hitchings were involved in making purine derivatives, a class of compounds found in the structure of DNA and other significant biomolecules. This important role for the purine framework made it an excellent starting point for drug discovery. Their work yielded drugs for malaria, organ transplantation, bacterial infections, and cancer and formed the basis for many more projects. Elion and Hitchings were also responsible for pioneering research methods that led to the development of AZT and antiretrovirals (critical for the treatment of HIV/AIDS). Scotsman Sir James Whyte Black was instrumental in developing two compounds (propranolol for heart disease and cimetidine for ulcers) that became the best-selling drugs in the world.

The key to what its practitioners call med chem is finding compounds with the desired activity, even if they’re weak, then varying their structures to make them more potent, more selective, and better tolerated by patients. Medicinal chemists must be nimble in response to new assay results, using any techniques they can think of to make new test molecules. “There are only two reaction yields,” goes one saying, “enough and not enough.”

Elion, Hitchings, and Black worked during the “classic age” of drug discovery, when medicinal chemists were learning how to optimize molecules toward specific targets. At the time, many compounds were tested directly in living cells or in rodent models of disease, since the practice of testing against pure cloned proteins had not yet been developed. But there’s value in testing phenotypically, i.e., looking for the desired effect in a living system without necessarily knowing all the details of how it happens. After many years of “target-driven” drug discovery, in which drugs are designed to interact with a known biological target, modern forms of phenotypic screening, a descendant of the techniques used by the scientists who made some of the most important contributions to clinical medicine in the twentieth century, are making a comeback.

George Hitchings and Gertrude Elion in an autographed photo from 1998.