JANUARY 22, 2001 VOL. 157 NO. 3

Bioinformatics
How to design a molecule
By UNMESH KHER

ALSO The Future of Drugs Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest • Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot • DNA Microarrays: The workhorse of genomic medicine • Bioinformatics: How to design a molecule • The Search for Cures: The fight against aids, cancer, mental illness, obesity, Alzheimer's

ALSO IN TIME COVER: The Future of Drugs Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest • Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot • DNA Microarrays: The workhorse of genomic medicine • Bioinformatics: How to design a molecule • The Search for Cures: The fight against aids, cancer, mental illness, obesity, Alzheimer's NORTH KOREA: Out of the Bag A German doctor's close encounters with the Hermetic Kingdom shed light on the miserable living conditions in one of the world's last Stalinist states. Plus, excerpts from his diary THAILAND: The New No. 1 The numbers are lining up for Prime Minister-elect Thaksin JAPAN: Murder on the Wards Fears that a killer nurse has been on the loose lead to calls for a more open medical system THE PHILIPPINES: A Load of Rubbish The streets of Manila are overflowing with uncollected trash HONG KONG: Surprise Farewell A top civil servant's resignation puzzles the territory MEDIA: A Guy on the Move Hong Kong mogul Jimmy Lai starts anew in Taipei RELIGION: Muslim Rebellion Japanese food-additive maker Ajinomoto comes under fire in Indonesia for an odd way of making MSG TRAVEL WATCH: Bear Necessities in Ancient, Spicy Chengdu

Drugs are molecular saboteurs. They exert their curative effects by gumming up the works of key proteins in the body. The compounds with the fewest side effects are the ones that drop their monkey wrenches selectively, slotting seamlessly into grooves on the surfaces of their target proteins—and leaving other proteins untouched.

It's not easy to design drugs that choose their targets this efficiently. In fact, it's so difficult that drug companies have hardly ever tried. They have relied instead on trial and error, testing hundreds of potential drugs in animals to find a few that actually cure without killing. But these molecular crapshoots are terribly wasteful, which is why drug designers are today turning to a fast-growing new area of computer science known as bioinformatics to fuel their endless quest for newer drugs and better targets.

GeneFormatics of San Diego, for instance, uses bioinformatic algorithms to help drug companies predict the function of proteins encoded by newly discovered genes. It does this by comparing the new proteins with those of known structure, generating a "fuzzy" picture of what each looks like. That, in turn, suggests what their biochemical functions may be—and how best to shut them down.

These fuzzy snapshots aren't always enough. When they are active, protein molecules may double over or twist into radically different shapes. Understanding their dynamics can be crucial to drug design, and for this, good computer simulations are invaluable. San Diego-based Structural Bioinformatics, for example, generates digital "movies" of how proteins writhe and bend when activated or ensnared by drugs, and identifies the small molecules that would best disable these moving targets.

The fact that computer-generated structures don't always work hasn't tempered the enthusiasm of drug designers. "Some knowledge is always better than no knowledge," says Arthur Olson of the Scripps Research Institute in La Jolla, U.S. And given the exponential growth of both computing power and data from the genome project, the technology can only get better.

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