Human Rationality Has Designs on Itself

Human rationality -- such as it is -- seems to be looping back upon itself. It looks as if the human brain may become the beneficiary of "rational drug design." The methods of rational drug design are advancing by leaps and bounds, so that we should expect some significant benefits quite soon.  Researchers at Tel Aviv University are focusing rational design to create drugs for Alzheimer's, Parkinson's, and Huntington's diseases.

Since Prof. Eldar-Finkelman linked GSK3 to insulin resistance in diabetes more than ten years ago, a race has been on among drug manufacturers to find a drug that can potentially turn off the harmful effects of GSK3. But rather than build on existing drugs, Prof. Eldar-Finkelman and her colleagues worked from the ground up. "I decided to take a completely different approach from all the big drug companies rushing to find the ultimate drug," says Prof. Eldar-Finkelman. "I designed my own."

Pre-clinical results have been positive, and the new drug does not exhibit dangerous toxic side effects, a problem with existing formulations. While L803-MTS cannot reverse the onset of a CNS disease once it has started, Prof. Eldar-Finkelman believes it can slow down the devastating effects of CNS diseases, like impaired memory and depression, or insulin-resistance.

"Ours is the first lab that showed the importance of GSK3 as a target in Type II diabetes, and was among the first to introduce a specific inhibitor against the GSK3," she says. "Our approach became so popular that today many pharmaceutical companies, big and small, are competing to work on a GSK3 inhibitor."

..."One important thing to note is that our drug acts differently than other compounds," she says. "Most GSK3 inhibitors are developed on the basis of ATP competitors. Ours are substrate competitors, meaning that they bind to a different site at the surface of the protein. This strategy is completely different, and yields a better and safer compound."

Prof. Eldar-Finkelman is now conducting additional pharmacological and toxicological tests on the new compound. She believes it will be a lead compound for treating CNS disorders, "because it was based on rational drug design. We started from scratch and thought through the design of a specific compound that would be safe and effective. Our aim is to slow the progression of CNS diseases, but the new drug might also be used as a preventative therapy," she adds. _SD

Rational drug design has come a long way in the past 10 years since Vertex began making waves. Advances in protein simulation, protein imaging, atomic force microscopy, haptics, bioinformatics, and other tools of research are allowing researchers to bypass tedious approaches such as "rapid screening" in order to aim directly at a drug target. Of course it is never really "either-or." In the end, many more tools will be developed, and all of the tools will be used to get us where we wish to be.