SEATTLE -- When searching for oil, one could drill randomly, but by starting in oil-rich areas such as Texas or the Middle East, the odds of success are much higher.
Traditionally, pharmaceutical researchers have had to drill at random when searching for molecular "oil fields" -- key sites on protein surfaces to be targeted for drug delivery. However, a molecular engineer at the Fred Hutchinson Cancer Research Center has devised a type of "dowsing" technique that could lead researchers, quickly and precisely, to areas of functional interest on proteins crucial to drug development.
The findings, in a paper by Jefferson Foote, Ph.D., assistant member of the Hutchinson Center's Human Biology Division, will be published Feb. 1 in the Proceedings of the National Academy of Sciences. Anandi Raman, formerly of the Hutchinson Center, also was an author on the paper. The research was funded by the National Science Foundation.
Central to Foote's discovery is a centuries-old, fundamental engineering concept called the "principal axes of inertia," a mathematical construct used to describe an object's three-dimensional properties. All objects have one or several axes upon which they can freely rotate, depending upon their shape. A spinning top is in alignment with its axis of inertia; a grocery cart with a wobbly wheel is not.
When Foote examined the principal axes of inertia in a wide variety of protein structures, he found their axes intersected areas that are most critical for biological function, from antigen-binding sites of antibodies to the catalytic sites of enzymes.
"If you have a newly discovered molecule and want to find out what it does and where its important parts are, this tells you where to start looking. It narrows down the search before you even begin," says Foote, who also found a strong correlation between axes of inertia and molecular regions used to bind DNA, protease inhibitors and virus proteins.
"The principal axes don't just graze the binding site; again and again I'd find that at least one would run right through the part of the protein that was most important for binding to a variety of ligands, from DNA to vitamins," says Foote, also an affiliate assistant professor of immunology at the University of Washington School of Medicine.
For example, when calculating the principal axes of inertia of p53, a tumor-suppressor gene, an axis was found to intersect amino acid 248, the site of the most common genetic mutation in human cancer.
Drugs work by interacting with a target molecule or protein that is crucial to basic bodily processes, from clotting blood to producing insulin. Typically, the drug molecule inserts itself into a crevice-like binding site on the target protein, much like a key fits into a lock. Once bound, the drug either enhances or inhibits the target protein's normal function. Finding the part of the protein that forms the binding site is crucial to drug design.
Foote has filed a patent application for his method of locating functional regions of proteins. This emerging technology may be used not only for finding drug targets but for developing molecular-modeling software to make the search that much easier.
Editor's note: Copies of the paper, "A Relation Between the Principal Axes of Inertia and Ligand Binding," are available to reporters from the PNAS Office of News and Public Information, (202) 334-2138 or at firstname.lastname@example.org.
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The Fred Hutchinson Cancer Research Center is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest. For more information, visit the Center's Web site at <www.fhcrc.org>.
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