As you’ve read so far, the most important A goals of modern pharmacology are also the most obvious. Pharmacologists want to design, and be able to produce in sufficient quantity, drugs that will act in a specific way without too many side effects. They also want to deliver the correct amount of a drug to the proper place in the body. But turning molecules into medicines is more easily said than done. Scientists struggle
to fulfill the twin challenges of drug design and drug delivery. Medicine Hunting 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 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 colchicine, 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 cells caffolding 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. 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.
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