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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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September 6, 2005

Crossing Your Fingers, Authoritatively

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Posted by Derek

I recall a project earlier in my career where we'd all been beating on the same molecular series for quite a while. Many regions of the molecule had been explored, and my urge was often to leave the reservation. I put some time into extending the areas we knew about, but I wanted to go off and make something that didn't look like anything that we'd done before.

Which I did sometimes, and then I'd often get asked: "Why did you make that compound?" My answer was simply "Because no one had ever messed with that area before, and I wanted to see what would happen." Reactions to that approach varied. Some folks found that a perfectly reasonable answer, sufficient by itself. Others didn't care for it much. "You have to have a hypothesis in mind," they'd say. "Are you trying to improve the pharmacokinetics? Fix a metabolic problem? Pick up a binding interaction that you think is out there in the XYZ loop of the protein? You can't just. . .make stuff."

I respected the people in that first group a lot more than I did the ones in the second. I thought then, and think now, that you can just go make stuff. In fact, you not only can, but you should. You probably don't want to spend all your time doing that, but if you never do it at all, you're going to miss the best surprises.

I take issue with the idea that there has to be a specific hypothesis behind every compound. That supposes amounts of knowledge that we just don't have. Most of the time, we don't know why our PK is acting weird, and we're not sure about the metabolic fate of the compounds. And we sure don't know their binding mode well enough to sit at our desks and talk about what amino acids in the protein backbone we're reaching out for. (OK, if you've got half a dozen X-ray structures of your ligands bound in the active site of your target, you have a much better idea. But if your next compound breaks new structural ground, off you may well go into a different binding mode, and half your presuppositions will go, too.)

I like to think that I've come to realize just how ignorant I am in issues of drug discovery. (In case you have any doubt, I'm very ignorant indeed.) But I still hear people confidently sizing up new analog ideas on the blackboard, though: No, that one won't bind well in the Whoozat region. Doesn't have the right spacing. And that one should be able to reach out to that hydrophobic pocket we all know about. Let's make that one first. (These folks are talking without X-ray structures in hand, mind you.)

Well, if it makes you feel better, then go ahead, I suppose. But this kind of thing is one tiny step up from lucky rabbit feet, for which there is still a market.

Comments (4) + TrackBacks (0) | Category: In Silico | Who Discovers and Why


1. John Johnson on September 6, 2005 8:40 AM writes...

I wonder what Einstein would have done had he listened to all the people who said, "You can't just make stuff!" I guess we would all be learning about Joe Bob's General Theory of Relativity.

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2. Tom Bartlett on September 6, 2005 9:18 AM writes...

I have a deep respect for the ability of nature to surprise us, and I think of myself as more of a cook than a chef. Add a dash of -halo or a smidge of -subs. Ph. But you have to do it in moderation and with taste. As for modelling, I love it and get a lot of value from it, but I've watched drug design people pick a -OH stereochemistry in HIV protease that turns out to be 10E4 WRONG based on decent crystal structures. You need to take everything with a grain of salt.

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3. Dr Snowboard on September 6, 2005 10:20 AM writes...

But I hope you'd prefer some kind of 'testiculation' rather than the often depressing 'because I could buy the monomer'....

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4. paul jones on September 6, 2005 11:26 AM writes...

As a synthetic chemist, I love to "just make things". Sometimes I read about a reaction I was unaware of (damn those named reactions, there are too many!!) , and try it out.... Other times I become tired of making seemingly endless analogs of our enzyme inhibitors and I take a day or two to "play in the lab". I find messing around fun, and it gives me a chance to remind myself why I chose chemistry in the first place.

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