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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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« The Voice of Experience | Main | Tailfins and All »

May 27, 2005

Compounds for the Sake of Compounds

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Posted by Derek

I've started my Memorial Day weekend early (thus the mid-morning posting time.)

One of the comments to the previous post mentions the "let's make these compounds because we can" attitude, and points out that this was the fallacy underlying the combichem boom (and bust.) True enough - I should have clarified my point by saying that the compounds I was recommending were much more targeted. They're related to a structural series that we know we're interested in, but we haven't made tested anything from this particular group yet.

And, truth be told, I don't mind the blue-sky let's-make-some-compounds approach, as long as it's done in moderation. Throwing some interesting structures into the screening files is never a waste of time, although there are often more pressing things to do.

I don't approve of sending in things that are poor candidates for starting off an optimization project, though. If something with a molecular weight of 1300 hits in your assay, there's often not much you can do about it. That's at least twice a reasonable molecular weight, and large compounds like that often can't be cut down to size. Their binding modes are complex, interesting, and almost impossible to deal with in any practical manner, unfortunately. Getting a handle on things like this is a longstanding problem in drug discovery, so unless you feel like solving it, you shouldn't add to it.

Similarly, anyone who sends in reactive compounds like acid chlorides deserves a whack over the head. Those things, assuming they don't fall apart in storage, will tear up most assays they're run in, and it's not like they're ever going to be drugs. Same goes for things like organotelluriums and other out-there elements. I have a fairly liberal attitude (silicon-carbon bonds are OK with me), but there's a limit. If you think someone's going to be happy when your nickel complex hits in their enzyme assay, you are not in touch with consensus reality.

The problem with the combichem boom wasn't always the underlying compounds, although some of them were stinkers (and most of them sure could have been cleaner.) I think the real trouble was how oversold the whole thing became. If you weren't buying or cranking out huge libraries, you were missing the gold rush. Vast untapped veins of drug leads were out there in those hills! Without the hype, things wouldn't have looked so bad. But hey, without the hype, most of those libraries wouldn't have been made. . .

Comments (6) + TrackBacks (0) | Category: Drug Assays


1. John Johnson on May 27, 2005 10:26 AM writes...

I liked combinatorial chemistry. But that's because I'm a combinatorialist (my official title is biostatistician because that pays the bills). When you have a hammer …

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2. Dr Snowboard on May 27, 2005 11:35 AM writes...

I agree completely that the problem with combichem was the hype and the implication that it would make iterative medicinal chemistry obsolete - I hope most chemists are now rewarded for a 'think and do' attitude rather than just blindly 'do'.

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3. PsychicChemist on May 27, 2005 11:50 AM writes...

At one point of time in our programs, compounds were being made just because some intermediate was commercially available, with little regard to if it made sense in the SAR set. That was somebody's way of showing how productive they were at making mostly useless compounds.

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4. Harry on May 27, 2005 11:23 PM writes...

Well- I wouldn't totally rule out compounds with weird elements. There was a compound called Ebselen (an organoselenium compound) that reached clinical trials as an NSAID IIRC. This is not totally counterintuitive- selenium acts a lot like sulfur and we know sulfur has a role in a goodly number of drugs. Of course, so did arsenic, mercury and tin, at one time.

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5. Petros on May 30, 2005 12:25 PM writes...

Well I remember going through compound registration cards to select compounds for addition to the screening collection and these included all the compounds submitted by the Agrochem chemists. (the company I was with being a late adapter of combichem so it had to boost screening numbers in other ways).

Now they were full of nasty reactive groups!

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6. Tom Bartlett on June 2, 2005 4:13 PM writes...

My experience working with Combo guys is that they approximately equal NON-combo guys in terms of ability to move a program forward; in spite of the fact the former make more compounds. Do you make more of the same, or shoot for great structural diversity? That is the eternal question. They work best either: doing early-stage blind library prep or 2) working VERY closely with the non-combo med chemists.

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