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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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May 6, 2011

In Which I Do Not Lose It, For Once

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Posted by Derek

PNAS recently came out with a special concentration of chemistry papers, and they're worth a look. The theme is the synthesis of chemical probes, which makes me think that maybe Stuart Schrieber can guest-edit an issue of Vogue next. Today I'm going to highlight one from the Broad Institute on diversity-oriented synthesis (DOS), and next week I'll get to some more.

OK, that was something of a come-on for regular readers of this site, who now will be listening for the sound of grinding wheels coming up to speed, the better to sharpen the Sword of Justice. I've said unfriendly things in the past about DOS and some of the claims made for it. The point of much of this work has been lost on me, and I'm a pretty broad-minded guy. (That word, in this case, rhymes with "sawed", not with "load"). The first flush (no aspersions meant) of papers in the field might just as well have been titled "Check It Out: A Bunch of Huge Compounds No One's Ever Made Before", and were followed up, in my mind, by landmark publications such as "A Raving Heapload of Structures You Didn't Want in the First Place" and "Dang, There Are Even More Compounds With Molecular Weight 850 Than We Thought". But does it have to be this way?

Maybe not. As I mentioned earlier this year, people are starting to compare DOS and fragment-based approaches. (I think that Nature dialog could have been more useful than it was, but it was a start). And this latest paper continues that process. It's using DOS approaches to generate smaller molecular weight compounds - fragments, actually. They're not tiny ones, more medium-to-large size by fragment-based standards, but they're under 300 MW.

And, importantly, they're deliberately designed to be three-dimensional - lots of pyrrolidines and fused-ring compounds thereof, homopiperidines, spiro-lactams, and so on. Many of the early fragment libraries (and many of the commercial ones that you can still buy) are too invested in small, flat, heterocycles. It's not that you can't get good leads from those things, but there's a lot more to life (and to molecular property space). This paper's collection is still a bit heavy on the alkenes to my taste (all those ring-closing metathesis reactions), but they've also reduced those for part of the library, which means that a screen of this collection will tell you if the olefin is a key structural feature or not. The alkenes themselves could serve as useful handles to build out from as well; a fragment hit with no ways to elaborate its structure isn't too useful.

As I said back in February, "I'd prefer that DOS collections not get quite so carried away, and explore new structural motifs more in the range of druglike space." That's exactly what this paper does, and I think its direction should be encouraged. This plays to the strengths of both approaches, rather than pushing either of them to the point where they break down.

Comments (12) + TrackBacks (0) | Category: Chemical News | Drug Assays


1. combichemgarbage on May 6, 2011 9:51 AM writes...

They're hooked up with Forma, filled with ArQule people. Remember ArQule, trumpeting automation of chemistry when their VP didn't even have a computer on his desk!

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2. Chris on May 6, 2011 1:08 PM writes...

"We decided that the construction of nonaromatic, high-sp3 content, and chiral fragments would be appropriate to test our hypothesis concerning the relevance of diverse 3D fragments. "

Don't they need to assay them to actually test their hypothesis?

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3. Mike W on May 7, 2011 1:04 AM writes...

""Check It Out: A Bunch of Huge Compounds No One's Ever Made Before", and were followed up, in my mind, by landmark publications such as "A Raving Heapload of Structures You Didn't Want in the First Place" and "Dang, There Are Even More Compounds With Molecular Weight 850 Than We Thought". But does it have to be this way?"

This absolutely killed me. The subject matter is interesting stuff, too, thanks for keeping track of this and giving it a fair second (third) hearing.

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4. Rick on May 7, 2011 9:30 AM writes...

I worked with a DOS-based company and found that, like many things, DOS can be an incredibly powerful discovery research asset in the right scientific and managerial hands. Unfortunately, it seems to have been mostly in clumsy hands. Blaming the technology is like the proverbial bad carpenter blaming his tools.

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5. imatter on May 7, 2011 4:51 PM writes...

"I'm a pretty broad-minded guy. (That word, in this case, rhymes with "sawed", not with "load")."


Are there any DOS hits that have gone through clinical trials?

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6. Rick on May 8, 2011 7:01 AM writes...

imatter (#5),
A "hit" making it through clinical trials is exceedlingly rare, regardless of the chemistry. Excluding nucleoside analogs, which I wouldn't count anyway, the last one I can think of is mevacor, which was a natural product hit.

As far as compounds produced using DOS, I am unaware of any that have made it all the way through clinical trials, which isn't surprising since the name DOS wasn't coined all that long ago. Would you count Infinity's geldanamycin, which made it into clinical trials? Infinity might, I'm not so sure.

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7. Useless Molecule on May 8, 2011 9:38 PM writes...

Totally pointless PNAS issue.

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8. Sili on May 9, 2011 2:29 PM writes...

I'm a pretty broad-minded guy. (That word, in this case, rhymes with "sawed", not with "load").
What am I missing here? You're too wellread and allusive for my tiny intellect to follow. Permalink to Comment

9. weirdo on May 9, 2011 3:07 PM writes...


"Broad" as in "Broad Institute" rhymes with "load".

"Broad" as in "broad-minded" rhymes with "sawed".

One of the problems of the Internet -- few pronunciation tools.

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10. Sili on May 9, 2011 5:02 PM writes...

Thanks - I completely missed the source in the first paragraph. Stupid me.

banana ...

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11. Dave_n on May 9, 2011 7:50 PM writes...


I hate to say it but Geldanamycin was first reported by Ken Rinehart in the late 1960s as an antiparasitic. Infinity's compound is nothing more than the hydroquinone intermediate in the metabolism of 17AAG (geldanamycin plus allylamine).

Nature's DOS yes, a mortal chemist's NOT!

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12. Rick on May 9, 2011 8:37 PM writes...

Dave_n (#11),
I know and I agree. I was trying to be discrete.

Your comment prompted me to realize that, living things do DOS all the time. It's hard to miss it when you look at a metabolic pathways chart (that's a chart biochemists used to have memorized way back in the 20th century).

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