T UCSON , A RIZONA - If the pharmaceutical companies are good at thing, there are tons of new molecules. In recent years they have embraced a technical producer of high-speed drugs known as combinatorial chemistry to multiply the new compounds by the millions. The problem is that few ever work against diseases. But at a meeting on the future of combinatorial chemistry here yesterday, a chemist proposed a new way to increase the chances :. Pair the most promising building blocks to produce compounds whose activity is much greater than the sum of their parts
a popular technique in combinatorial chemistry is to start with a handful of molecular building blocks then connecting in all possible combinations. As expected, the number of compounds quickly becomes unwieldy. Using all currently available building blocks, the researchers could produce a staggering 10 60 small combinations druglike molecules.
To make things more manageable, Jonathan Ellman of the University of California, Berkeley, and his colleagues have focused on the components with the best chance of success. They are turned toward a class of molecular building blocks called oximes which are common components of pharmaceuticals. The researchers screened a library of just over 300 oximes for their ability to bind to a cell-signaling protein called Src, which is considered too active in cancer and osteoporosis. When tested alone oximes, about 10% showed moderate ability to inhibit Src in the test tube. However, when these have been linked to poor binding, the story changed dramatically. The team synthesized Ellman about 4000 pairs of oxime and found a handful of potent inhibitors of Src, a success rate that usually requires much more compounds.
The new approach is powerful because it has the potential to produce drugs that bind to more than one part of a target molecule, said Sheila DeWitt, a combinatorial chemist Arqule, a company Woburn, Massachusetts. This could lead to a new way to make ultra powerful drugs. "If it works, it will have enormous value," she said.
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