Folding Forum

'In the study, a team of chemists at the University of California, San Francisco, found that these candidate drugs form large, unwieldy clumps themselves, rendering them useless as targeted therapy against amyloid in the brain.'
http://news.yahoo.com/s/hsn/20080127/hl ... beadeadend

Edited by susato, 26 May 08: Above link is broken, link in post below is irrelevant.
Try this link instead
PS Thanks Dr. Branson for a most helpful reply.

I too agree with this.These are useless which will never work.
http://www.mydepressionmedication.com/a ... epressants

With all drug screening its important to have a counter screen to determine if the result you see is a 'false positive'. I.e its having an effect in your assay, but possibly for the wrong reasons, such as interfering with the functional readout etc, or in this case binding non specifically to the protein.

In order to weed out such compounds, we always screen our molecules in development against the assay mentioned in this article and another unrelated system. These molecule will interfere with these other systems and bind non-specifically to all proteins. We don't follow up on such compounds.

In general if you are reading articles about computational drug design, remember just as in high throughput screening the results might be artifactual. So always look to see if the authors of the study did the relevant control experiments.

In addition to aggregate formation, another key issue with alzheimers compounds is they may act simply by chelating metal. (although metal chelation is a valid strategy, and that's another debate) We are looking for compounds that act via binding to the abeta protein. Compounds that chelate metal may look like they reduce aggregation, but they don't bind to the protein directly and simply act by reducing the concentration of metal ions (Ca, Zn, Cu etc) in solution, thus they reduce aggregation only indirectly. We also perform a counter screen to weed out such molecules.

cheers

Kim

edited by susato to consolidate two posts, w/ Dr. Branson's OK

Kim Branson wrote:Compounds that chelate metal may look like they reduce aggregation, but they don't bind to the protein directly and simply act by reducing the concentration of metal ions (Ca, Zn, Cu etc) in solution, thus they reduce aggregation only indirectly. We also perform a counter screen to weed out such molecules.

Soon your MD colleagues won't know you from a chemist, Dr. Branson!

D