While sometimes the discovery of potential medicines falls to researchers' good luck, most often pharmacologists, chemists, and other scientists looking for new drugs plod along methodically for years, taking suggestions from nature or clues from knowledge about how the body works.
Finding chemicals' cellular targets can educate scientists about how drugs work. Aspirin's molecular target, the enzyme cyclooxygenase, or COX (see page 22), was discovered this way in the early 1970s in Nobel Prize-winning work by pharmacologist John Vane, then at the Royal College of Surgeons in London, England. Another example is colchicines, a relatively old drug that is still widely used to treat gout, an excruciatingly painful type of arthritis in which needle-like crystals of uric acid clog joints, leading to swelling, heat, pain, and stiffness. Lab experiments with colchicine led scientists to this drug's molecular target, a cell-scaffolding protein called tubulin. Colchicine works by attaching itself to tubulin, causing certain parts of a cell's architecture to crumble, and this action can interfere with a cell's ability to move around. Researchers suspect that in the case of gout, colchicine works by halting the migration of immune cells called granulocytes that are responsible for the inflammation characteristic of gout.
A Drug By Another Name
As pet owners know, you can teach some old dogs new tricks. In a similar vein, scientists have in some cases found new uses for "old" drugs. Remarkably, the potential new uses often have little in common with a drug's product label (its "old" use). For example, chemist Eric Oldfield of the University of Illinois at Urbana-Champaign discovered that one class of drugs called bisphosphonates, which are currently approved to treat osteoporosis and other bone disorders, may also be useful for treating malaria, Chagas' disease, leishmaniasis, and AIDS-related infections like toxoplasmosis.
Previous research by Oldfield and his coworkers had hinted that the active ingredient in the bisphosphonate medicines Fosamax®, Actonel®, and Aredia® blocks a critical step in the metabolism of parasites, the microorganisms that cause these diseases. To test whether this was true, Oldfield gave the medicines to five different types of parasites, each grown along with human cells in a plastic lab dish. The scientists found that small amounts of the osteoporosis drugs killed the parasites while sparing human cells. The researchers are now testing the drugs in animal models of the parasitic diseases and so far have obtained cures—in mice—of certain types of leishmaniasis. If these studies prove that bisphosphonate drugs work in larger animal models, the next step will be to find out if the medicines can thwart these parasitic diseases in humans.
Current estimates indicate that scientists have identified roughly 500 to 600 molecular targets where medicines may have effects in the body. Medicine hunters can strategically "discover" drugs by designing molecules to "hit" these targets. That has already happened in some cases. Researchers knew just what they were looking for when they designed the successful AIDS drugs called HIV protease inhibitors. Previous knowledge of the three-dimensional structure of certain HIV proteins (the target) guided researchers to develop drugs shaped to block their action. Protease inhibitors have extended the lives of many people with AIDS.
However, sometimes even the most targeted approaches can end up in big surprises. The New York City pharmaceutical firm Pfizer had a blood pressure-lowering drug in mind, when instead its scientists discovered Viagra®, a best-selling drug approved to treat erectile dysfunction. Initially, researchers had planned to create a heart drug, using knowledge they had about molecules that make blood clot and molecular signals that instruct blood vessels to relax. What the scientists did not know was how their candidate drug would fare in clinical trials.
Sildenafil (Viagra's chemical name) did not work very well as a heart medicine, but many men who participated in the clinical testing phase of the drug noted one side effect in particular: erections. Viagra works by boosting levels of a natural molecule called cyclic GMP that plays a key role in cell signaling in many body tissues. This molecule does a good job of opening blood vessels in the penis, leading to an erection.