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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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May 9, 2012

More Reaction Discovery (Now With Antibody Detection)

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Posted by Derek

I've written here before about reaction discovery schemes, and the reaction to those reactions has been, well, mixed. I like them, some other people like them, but some other people are quite offended by the "random search" mentality behind these ideas.

Well, prepare yourselves for another technology for exploring the wild blue yonder. A new paper in Angewandte Chemie from a group at the CEA (Gif sur Yvette, France) outlines an immunological detection scheme. They have antibodies to an imidazole derivative, and antibodies to a phenolic moeity as well. So both structures are attached to a range of functional groups and combined with heat and/or metal catalysts to see if anything happens. A sandwich assay at the end with the different antibodies gives you a yellow color only if a compound has been formed that has both ends present; that is, if a coupling reaction of some sort has occurred.

They ran 3360 reactions, each on a 100 nmol scale (there's the sensitivity of the antibodies for you). Two new reactions were discovered - an isourea synthesis (which can lead to benzoxazoles) and an alkyne reaction leading to thiazole derivatives. Neither of those is going to set the world of organic chemistry ablaze, but as a proof of concept, I'm convinced that this technique can work. So what do you do with it next?

One plan looks to be discovering new bioorthogonal reactions, couplings that can take place either inside or on the surface of living cells. The immunological detection is so sensitive that products can be teased out of all sorts of messy mixtures, apparently even cell lysates. I'd also encourage them to try some other conditions, such as various photochemical setups, to see what might be out there - it's a much less explored field than copper-catalyzed coupling reactions.

Like it or not, I think we're going to be seeing more of this sort of work. We might as well make the most of it!

Comments (3) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. ProteinChemist on May 9, 2012 11:07 AM writes...

Since I don't know as much about small molecule specificity, is your "(there's the sensitivity of the antibodies for you)" comment a compliment or detraction? I work with a lot of antibodies, and I can tell you that if I had one with only 100nM affinity I would be a very unhappy scientist. Getting to the meat of the issue, though, this seems like a difficult sell. Are they banking on their detection structures being non-reactive? Can you assume that if you are searching for novel mechanisms? Also, this would be limited just because of antibody size and steric effects. A reaction that brings the two moieties together could cause a false negative in the panel just because both detection antibodies cannot fill the same space. I like the idea, but sub-protein sizes seem a bit rough for a sandwich assay.

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2. mass_speccer on May 9, 2012 1:37 PM writes...

This isn't an area I'm hugely familiar with, but it sounds like a pretty good idea.

I assume the advantage over screening by LC-MS is to do with throughput, or is there something more than that?

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3. Wile E. Coyote, Genius on May 9, 2012 8:02 PM writes...

How does the heating part work? Doesn't that denature the antibodies? The way I read the blog (didn't go to the paper), is it that antibodies are put in up front, and then heating or metal catalysts?

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