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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

« EMBL Chemical Biology: Labeling Proteins | Main | EMBL Chemical Biology: Unnatural Amino Acid Labels »

September 27, 2012

EMBL Chemical Biology: Discovering Catalysts

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Posted by Derek

Right now, there's a talk going on from Helma Wennemers of the ETH. She's working on small peptidic catalysts for organic reactions, what one might think of as "mini-enzymes". They're certainly not as wildly effective as real enzymes, but they're a lot easier to find and modify. Here's an example, which has been extended to solid-supported catalysts here. And whenever I see a solid-supported catalyst, I think "Can you use that for flow chemistry?" I was glad to see that they're done just that - I don't think that work has been published yet, but it seems to work pretty well.

Chemistry like this is a good reminder of just how many catalysts remain to be found. I don't see any reason, a priori, for any reaction to be out of bounds for enzymatic-type catalysis. You have functional groups that can participate in some reaction mechanisms (as is the case for the proline nitrogen in the above work), you have stabilization of transition states, you have sheer physical proximity/effective molarity, and probably other effects that people are still arguing about. Eventually we'll get good enough to design such things, but for now, a combination of design and what I might call "enlightened brute force" looks like the way to go. I'd like to see someone pick some reaction types that are not catalyzed enzymatically and apply these techniques to make something we've never seen before. If we could figure out how to get new metallic centers into these this things (imagine an enzymatic palladium catalyst!), we could really do some wild chemistry. Mind you, I'm not the one who would be trying to get that funded.

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


COMMENTS

1. HK on September 27, 2012 12:05 PM writes...

Refer to the work of Scott J Miller (Yale) for some pretty neat work along these lines. They use tetra- and pentapeptides to catalytically and site-selectively modify vancomycin. I'd also love to see his work applied so solid-supported catalysis - if your peptide's already on a bead, might as well, right?

Also, there was a really cool paper in Science in 2010 with a who's-who list of authors (Houk, Baker, Michael, etc etc) on the de novo development and synthesis of a Diels-Alderase. They predicted an enzyme in silico that would catalyze their desired Diels-Alder reaction, made a few iterations of that enzyme, and found that it did more or less exactly what they had predicted it would do. Blew my mind.

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2. rhodium on September 27, 2012 1:29 PM writes...

If you look at Schrock's olefin metathesis catalysts you see Mo, already found in native cofactors and oxygen and nitrogen ligands. I would not be surprised if someone finds an enzyme doing olefin metathesis (say to make novel unsaturated lipids). Nature knows how to make carbenes (thiamine) after all. As far as palladium enzymes go, I have never forgotten John Osborn, in his organometallics class, wishing that life had evolved first near South Africa so biochemistry would have used the platinum group metals.

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3. gippgig on September 28, 2012 2:43 AM writes...

Anybody look at similar N-terminal proline-containing peptides to selectively catalyze aldol condensations? I've been wondering about that for a while. (Why isn't proline organocatalysis common in nature? Probably because it's not trivial to get N-terminal proline since the N-terminal methionine isn't cleaved from a protein that starts Met-Pro. There would have to be a specific X-Pro protease.)
There are enzymes that contain tungsten.

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