But now “rational drug design” has taken hold in the laboratories of dozens of small pharmaceuticals firms. That’s not to say that drug research has been irrational-just serendipitous. The new tools of biotechnology and computers make it more scientific. The potential payoff-. drugs that are cheaper, more effective and safer than those in the medicine cabinet today. The new techniques lend themselves particularly well to some illnesses–cancer, heart disease, AIDS-that have mostly resisted the pharmacologists’ old tricks.
Most drugs work mimicking part of a natural substance, overall a molecule that fits into a “receptor” the way a key fits into a lock, and either promotes or hinders a physiological process. The antianxiety drug Valium, for example, fits a receptor on nerve cells that influences the neurons’ activity; the Valium-receptor linkup slows the firing of the cells and thus relaxes the patient. The shape of antibiotics interferes with material that bacteria need to reproduce; when the germs can’t multiply, the infection subsides.
Mimicking these lock-and-key molecules is the goal of rational drug design. “This science is in its infancy,” says Peter Johnon, president of Agouron Pharmaceuticals n San Diego. But “we’re starting to learn he rules that govern the interactions between drugs and their targets.” In the first step, biotechnologists use recombinant DNA, X-ray crystallography and nuclear magnetic resonance to determine the shape of the target receptor-the lock. Chemists then use computers to design new drug molecules-keys-to fit. The same computer, using artificial intelligence, can do preliminary testing right on screen to gauge efficacy, potency and even side effects. Says Michael Ross, president of Arris Pharmaceuticals in San Francisco, " We want a computer that will say, ‘That’s just like the last 15 molecules you made. Don’t bother’." A $50,000 program from software maker BioCAD lets drug designers create molecules even when they don’t know precisely which receptor sites they’re trying to fit: the program just keeps suggesting variations until it gets a match. “All of us,” says Arris’s Ross, “are trying to make this less of a gamble and more of a process.”
The first roll of the dice is whether the new compound will attach to the right receptor and do what it’s supposed to. Sometimes adding a molecular tail of glucose, water, peroxide or some other clump of atoms to the potential drug can mean the difference between sizzle and fizzle. So traditionally, researchers mix thousands of variations on the candidate drug, then study each one for the desired biological activity. Each compound can cost thousands of dollars to make and hours of lab time to test. But at the Affymax Research Institute in Palo Alto, Calif., thousands of candidates are simultaneously painted onto a silicon chip a third of an inch across, using the technology that creates electronic circuits on computer chips. The chip also holds the receptor. Then a laser beam scans the surface of the chip, examining each tiny sample to detect whether any reaction has occurred: if a possible drug has bound to the receptor, a fluorescent dye lights up. In minutes, thousands of samples are screened-resulting in a few dozen promising compounds. “We can do in a month,” says founder Alejandro Zaffaroni, “what used to take companies five years.”
The proof, of course, is in the patient, and the first of the new crop of rational drugs are entering human trials. Agouron has innovative drugs for both cancer and AIDS under development. In Cambridge,Mass., Vertex has an AIDS drug and an anti-inflammatory that may have applications from rheumatoid arthritis to toxic shock syndrome. In Branford, Conn., Neurogen Corp. is nearly ready to launch into clinical trials an anti-anxiety drug that may have minimal side effects. Arris is on the trail of atherosclerosis and asthma treatments. And observers are optimistic. “It’s very likely that one or more of these companies will be a brand name in 10 years,” says James McCamant, editor of the Medical Technology Stock Letter. " The potential of the area is hard to imagine," says Agouron’s Johnson.
With all this computerized creativity, do we still need rain forests to inspire new drugs? Fortunately, yes. A compound such as the cancer drug taxol, derived from the bark of the Pacific yew tree, is so complex that it’s unlikely someone would have invented it from scratch. “These techniques augment but don’t replace the benefits we get from biological diversity,” says Gerry Maggiora of Upjohn Laboratories. “We humans are clever, but not that clever.” Even so, in a world of costly health care struggling against intractable diseases, ration a drug design sounds like a promising start.
