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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: Greasy Labels | Main | EMBL Chemical Biology: Substrate Activity Screening »

September 27, 2012

EMBL Chemical Biology: George Whitesides on Ligand Binding

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Posted by Derek

Now the conference day is winding up with a big talk by George Whitesides. He's talking about his thoughts on enzyme function, with reference to his group's work using carbonic anhydrase as a model. He praises its stability ("a ceramic brick") and other characteristics, as you might expect from someone who's published an entire review on its use in biophysical studies.

So what makes compounds bind to enzyme sites? His take on the hydrophobic effect is that he thinks it's due as much (or more) to changes in networks of water molecules, rather than just the release of structured water at the protein-ligand contact. The latter is important, for sure, but not the whole story. "There is no one hydrophobic effect", he says, "there are many hydrophobic effects".

Another quote: "There ain't nothin' like water", and I definitely agree. We're used to water, since it's the most common chemical substance that we deal with in our lives, but water is weird.

And there's a lot we don't know about it still. For example, Whitesides has just pointed out that we have a reasonable understanding of surface tension in the bulk phase - but not at all for molecular-sized holes. This is crucial for understanding ligand behavior. His view of protein-ligand binding, he says, is very water-centric. . .

Comments (9) + TrackBacks (0) | Category: Chemical Biology


COMMENTS

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

prof. William von Eggers Doering recounted his excitement when as a young professor he got to go to Europe and meet with Lars Onsager. At last, he thought, he would understand solvent effects. So they met, and they talked and they talked. And he came back to the U.S., and spent the rest of his long career working in the gas-phase.
Maybe in the 21st century, George finally has the tools to understand solvent effects in depth. Certainly anyone who has tried to evaluate the binding strength for a novel ligand in-silico has encountered the strong (overwhelming!) dependence on how one models water.

Permalink to Comment

2. eugene on September 27, 2012 3:29 PM writes...

Now why couldn't Whitesides give that lecture when he was a plenary speaker here, since it sounds interesting, instead of the crap that was 50 minutes of his view on the nature of research and had most of the audience leave or fall asleep. I think we got robbed.

Permalink to Comment

3. Anonymous on September 27, 2012 3:45 PM writes...

Everytime I shake a bottle of oil and water, I am treated to a front row seat for observing the hydrophobic effect in action. The forces in play here must really be profound because within about ten seconds my dispersion has separated back into two phases. I visualize my drug molecules as super micro oil droplets that really want out of that water and nicely nestled into a snug greasy pocket on a biotarget, assuming I can actually separate my little grease balls from each other in the first place.

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4. luysii on September 27, 2012 4:23 PM writes...

From Voet "Biochemistry" 3rd Ed. p. 39

"Water is so familiar, we generally consider it to be a rather bland fluid of simple character. It is, however, a chemically reactive liquid with such extraordinary physical properties that, if chemists had discovered it in recent times, it would have undoubtedly been classified as an exotic substance."

Permalink to Comment

5. Fred on September 27, 2012 5:27 PM writes...

Once again the mystery of water returns to the pipeline and Luysii is there with an awesome insight or link. My question. How come very few academics study water? How do we think we can understand life (biomechanisms) without really understanding water? what i have found is the people that study water are out of the mainstream and have a hard time finding funding. I would love to hear med chemist comments (coughderekcough) on Dr Gerald Pollack work at UW and how it relates to drug discovery and our understanding of cells and life in general.

Permalink to Comment

6. The Rock on September 27, 2012 5:40 PM writes...

Off topic, but certainly outrageous considering this blog's interest in the ongoing sirtuin debacle.

http://www.science-fraud.org/?p=750

Congratulations Gizem...

Permalink to Comment

7. MJ on September 27, 2012 7:27 PM writes...

Fred - Have you seen Philip Ball's excellent blog on that very topic? You can find it at http://waterinbiology.blogspot.com/ He doesn't update as often as he did at the start of the blog, but he's still been updating about once every other month over the last year and change. Not sure if I'd agree with your characterization of the field as not mainstream, though - there are plenty of "mainstream" research groups interested in this very topic, although perhaps this is a matter of perspective.

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8. Curious Wavefunction on September 27, 2012 9:43 PM writes...

#5: How come very few academics study water?

Actually many of them do. The writer Philip Ball has a whole blog devoted to academic studies on water. Google "Water in Biology" and you will find it.

Permalink to Comment

9. a. nonymaus on September 28, 2012 12:20 PM writes...

#5: How come very few academics study water?

Another (more general) example is the work by John D. Roberts at Caltech on competition between intramolecular and solvent-solute hydrogen bonding in water and other solvents.

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