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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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« Compounds for the Sake of Compounds | Main | Modeling the Modelers »

May 30, 2005

Tailfins and All

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Posted by Derek

As a drug discovery project goes along, different labs tend to claim different parts of the molecule to work on. They run all sorts of variations within their territory, usually keeping the rest of the molecule at some sort of agreed-on default setting or two. Likely as not, they'll find something along the way that makes things a lot better (more potent, longer-lasting in the blood, etc.)

The natural thing to do is to combine these things, to make what I've long called a greatest-hits molecule. "Let's put that acyl group that Jim likes on there, and put best of the N-aryls from Sue's lab, and over on the side chain we'll have that solubilizing group that works so well on Wei's molecule. . .can't miss!"

Actually, these things miss about as often as they hit. Rarely have I seen a project where you can mix-and-match with confidence. You have to try these combinations, but after you've started to fill out the matix, you find that your compounds act more like this: "Well, the acyl group is good, as long as you don't have a heteroaryl group over here, but if you do then you can get away with the chloro on this position, but not if you have the amine side chain, except when there's an alpha-methyl. . ."

What's going on is that your molecules probably don't have just one way of fitting into their binding pocket in the target protein. They might have two modes; they might have twelve. There's no way to be sure, and I say that with no intention of offending the molecular modelers and their computer simulations. (But hey, if the shoe can be docked onto your foot in a low-energy conformation, wear it.) Many of these binding modes are going to have mutually incompatible features, and you can make your head vibrate trying to reconcile them into a single coherent picture.

Comments (2) + TrackBacks (0) | Category: Drug Development


1. John Johnson on May 31, 2005 10:59 AM writes...

This sounds like the drug discovery version of a long-time debate in industrial statistics: factor-at-a-time experimentation vs. factorial designs (which explore interaction effects, if you follow the advice of the textbooks).

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2. jeet on May 31, 2005 12:15 PM writes...

So how good/ much value is added by the computer simulations?

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