Feb. 27, 1998 Using metal atoms as molecular matchmakers, University of Rochester chemist Benjamin Miller has devised a new way of forming a nearly endless variety of potential drugs, then plucking out the most promising candidates for further study.
Miller's system shifts the burden of the most painstaking drug-development work off the shoulders of technicians and onto tiny molecules, which assemble themselves into countless combinations and then go through a Darwinian process that closely mirrors how nature finds the best compound for a job. If the technology can be expanded for industrial use, it would offer a faster way for chemists to create and screen potential new drugs.
"The approach shows great promise because it's fundamentally more efficient," says Paul Wender, professor of chemistry at Stanford University and an expert in the synthesis of biochemical and medicinal compounds. "The Miller group has clearly shown that this approach makes sense and that it can work. Nature is a huge biodiversity generator, and they've found a way to mimic this process in the laboratory."
Miller's technique relies on atoms of transition metals, such as zinc or cadmium, to build vast libraries of thousands of potential drugs. Just as a skilled host can facilitate socializing between strangers at a cocktail party, these atoms of zinc and cadmium pair up small molecules known as monomers, searching for a fruitful combination. Everyday chemistry then goes to work to "decide" which of the resulting compounds best matches the prospective drug's DNA, RNA, or protein targets, which cause disease. The very best match elbows out all the others to latch onto the target molecule.
"With our technique, we try to find molecules to bind receptors in much the same way nature has for millions of years," says Miller, an assistant professor of chemistry. "We take a receptor we want to target, add many little molecules to it, and see which ones are best at binding the receptor."
The work is the latest development in the burgeoning field of combinatorial chemistry, which many pharmaceutical firms are using to ferret out new compounds to take aim at disease- producing DNA and RNA sequences and proteins. Miller and graduate students Bryan Klekota and Mark Hammond showed in a recent issue of Tetrahedron Letters that the new method works for finding drugs to target and bind to double- stranded DNA made up of a single repeating base. They're now examining whether the technique can be used to create drugs to inactivate ras and her-2, genes that play roles in some forms of cancer.
Finding new drugs is a numbers game, and the odds shoot up dramatically when chemists can peruse thousands or even millions of candidates. Currently technicians and customized robots search for potent new drugs by systematically pairing up chemicals in test tubes, meaning days and days of repetitive lab work to build up a database of compounds; then they fish out the useful ones. Miller's work, funded by the National Science Foundation, Research Corporation Technologies of Tucson, Ariz., and the University, relieves this drudgery by using metal atoms to instigate chemical self-assembly, a relatively new technique that lets molecules put themselves together piece by piece.
The metal matchmakers are versatile, allowing molecules to come apart as readily as they form. Just as might happen if the two guests brought together at the cocktail party don't hit it off, the two monomers can easily break away from their metal mooring if the resulting compound doesn't succeed in binding the target molecule. This gives them the chance to try their luck in a new alliance. With current methods, there's no way to go backward and rework the drug candidates into useful compounds; researchers have to start from scratch again and again.
Wender, who was Miller's doctoral advisor at Stanford, says that Miller's concept might also find a niche in the production of next-generation chemicals other than drugs. "Basically all one needs to do is develop a group of molecules that can self- assemble and a selection system to pull out the molecules that are desirable," he says. "It's easy to imagine ultimately producing a variety of materials with superior properties through such an evolutionary process of molecular self-assembly."
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