Sunday, September 12, 2010

Lock and Key

Recently I finished reading The Billion Dollar Molecule which is the true story how one small drug company got its start in the early 90s, a time when many biotechs and small companies just popped up. I know people at this particular company and also had heard several of the main characters speak at various meetings so I found this book particularly interesting. One person is associated with the research institute that my SIL works at. Basically what this company brought to the table is that they were going to design drugs to specifically fit into a receptor aka structure based design. This was not a new concept even then.

When medicinal chemists try to explain what they do (beyond the I make drugs), they invoke the old lock and key metaphor: there is a lock (could be an enzyme, a receptor...) and we try to make the key that fits into the lock. There are a few problems with this metaphor (and structure based design in general). One is figuring out what this 'lock' looks like. Having a crystal structure of the enzyme is useful here. What are the binding regions of a receptor are a bit harder to picture. You can figure out what binds and what doesn't and construct a model from that. Another problem is that both the lock and key are not static. They both can bend and twist. Another problem is even if you find the key, by the time the body metabolizes it, it might be something else. As time goes on and computers become more powerful, they (the industry) is getting closer to making this work. In the meantime, we used to have modelling meetings which I used to hate. We'd sit around in a dark room wearing our 3-D glasses that gave me a headache after 5 minutes. Our alleged receptor, all pretty and colorful, would seem to float above the table. This always impresses outsiders. We had to propose targets in advance. The computational chemists would feed them into the computer and then see how they would fit into 'the lock'. On several occasions I was told that what I proposed definitely wouldn't work despite my intuition and I would make them anyway and guess what, they were good. So I was cynical of the whole modelling exercise. Once it was announced we were closing down, these modelling sessions were suspended. Back to my intuition on what to make which was fine by me.

In the book, the lock was a protein involved in immunosuppression. If this company found the right key, a successor to Cyclosporin could be found. Cyclosporin enables people to receive organ transplants so they don't reject their organs but the side effects are not fun. Clearly a better drug is needed. This company led investors to believe they had 'the lock' identified; finding the key would be simple. But as it turned out, the 'lock' wasn't anything useful. Fortunately for the company, they quickly found other projects to justify their existence.

Watching UM beat Notre Dame was fun yesterday. Josh had a UM party. Did he go there? No, but still it is his favorite team. Who did go there? 4 generations of us starting with my grandfather, father, me and Shanna (for 2 years, she graduated from MSU).

It is beautiful out here today. I ran out into the country. For lunch we will meet up with Josh and Julia for Cuban food.


Kathy;Chris said...

Sue back in the PD muscarinic agonist days, I recall that the computer modeling folks seemed to bat ~1,000% when telling us what compounds we should NOT synthesize, but there was NO real ability to predict what compounds we should create that WOULD be active.....regardless of 3D glasses and glitzy presentations....

Teri Bernstein said...

Son In Law ? I am as feeble with acronyms as I am with icons...I am in Patterson, CA, BTW Ms. Tracker...en route home from dropping off Molly at Pierce Co-op. Do all co-ops smell the same?

Sue in Italia/In the Land Of Cancer said...

Teri,according to my tracker, you are in Hayward CA, whereever that is. You guessed SIL correctly. I'm sure you'll miss Miss Molly. I know I do..she's such a gem! Oh to be living back in the co-op arguing whether fish is a meat as it doesn't eat grain! I am guessing her co-op is at least smoke free unless Ms. Spooner is still a student.
I was on that same muscarinic agonist project too for a while. Yep it's hard to make one. We were successful making a muscarinic ANTagonist though. A certain chemist (who co-incidentally defected to the Billion Dollar company) got some in one eye and came running to us to see if we thought something was wrong with his eyes. Well one was dilated normally but the other, the pupil was so small, you could barely see it. Very freaky. Get that boy some belladonna!


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