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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (362)	11/21/1999 7:34:00 PM
From: Casaubon	Read Replies (1) \| Respond to of 1169

I am chemistry-challenged, and I consider this discussion between you and Miljenko to be unfair. Well, here's a real simplistic version. We knew FKBP12 was "involved" in the immunosuppressive action of FK506. We knew the structure and shape of FK506 and FKBP12. Like some hack locksmiths, we figured if we could make "new" molecules conform to the shape of FK506 (the key) it should fit into the lock (FKBP12) just as well as the original key. Well we made great "key" mimics but they didn't work the lock (here the lock is more rigorously defined as immunosuppression). Well it turns out the lock wasn't simply FKBP12, but rather a larger more complex group of proteins acting together. The lock really turned out to be dependent on the activity of calcineurin (not FKBP12). So, we were only designing drugs to fit a part of the lock (FKBP12), not the whole lock (calcineurin plus other relevent proteins). Trying to mimic the activity of FK506 (a very complex molecule structurally) with "simpler" keys proved to be too challenging. The real problem was that we needed to fit two "locks" simultaneously. Both FKBP12 needed to be tightly bound to our molecules while simultanoeusly presenting a proper surface, of the designed drug, to bind calcineurin. The dual key solution to the dual lock problem proved too difficult for our efforts. We could make wonderful inhibitors (binders or "keys") to FKBP12, but we were never able to simultaneously present a proper binding surface ("dual key") to calcineurin ("dual lock"). Even after solving the crystal structure of calcineurin we could not design good enough keys to fit both locks. However, we ended up with a wonderful library of FKBP12 binders (some of which ended up showing some neurotrophic facility). Of course we also ended up showing that binding of FKBP12 was not necessary for neurotrophic activity.