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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

« Recommended Books For Medicinal Chemists, Part One | Main | Climategate and Scientific Conduct »

November 30, 2009

More Binding Site Weirdness

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Posted by Derek

Now here's an oddity: medicinal chemists are used to seeing the two enantiomers (mirror image compounds, for those outside the field) showing different activity. After all, proteins are chiral, and can recognize such things - in fact, it's a bit worrisome when the enantiomers don't show different profiles against a protein target.

There are a few cases known where the two enantiomers both show some kind of activity, but via different binding modes. But I've never seen a case like this, where this happens at the same time in the same binding pocket. The authors were studying inhibitors of a biosynthetic enzyme from Burkholderia, and seeing the usual sorts of things in their crystal structures - that is, only one enantiomer of a racemic mixture showing up in the enzyme. But suddenly of their analogs showed both enantiomers simultaneously, each binding to different parts of the active site.

Interestingly, when they obtained crystal structures of the two pure enantiomers, the R compound looks pretty much exactly as it does in the two-at-once structure, but the S compound flips around to another orientation, one that it couldn't have adopted in the presence of the R enantiomer. The S compound is tighter-binding in general, and calorimetry experiments showed a complicated profile as the concentration of the two compounds was changed. So this does appear to be a real effect, and not just some weirdo artifact of the crystallization conditions.

The authors point out that many other proteins have binding sites that are large enough to permit this sort of craziness (P450 enzymes are a likely candidate, and I'd add PPAR binding sites to the list, too). We still do an awful lot of in vitro testing using racemic mixtures, and this makes a person wonder how many times this behavior has been seen before and not understood. . .

Comments (4) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News | Drug Assays


COMMENTS

1. SP on November 30, 2009 1:34 PM writes...

That sounds like something that could happen fairly often in sites whose natural ligands are some sort of dimer.

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2. Chemjobber on November 30, 2009 3:39 PM writes...

For those of us who are less experienced, what is a typical binding site size? How many orders of magnitude larger than the average binding site is a P450 binding site?

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3. fragment_boy on November 30, 2009 4:36 PM writes...

TBH I cant see why this is in Angewandte (though it could be classed as one of those weird things they love to publish)

In fragment experiments you can get multiple binding modes - in this case they just have multiple binding modes for different enantiomers which is interesting but not that exciting.

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4. philip on December 1, 2009 11:14 AM writes...

A few years ago I saw a crystallography talk about a nanomolar binder that was badly disordered in the binding site. What this said to me is that there is a huge amount of energy to be gained just by taking a greasy molecule out of water and "dissolving" it in a hydrophobic binding pocket. So if you float hydrophobic molecules into an environment where the only places to go are hydrophobic sites, that's what will happen. The fact that enantiomers stick to a protein in different ways is not surprising at all. And it probably has little or no instructive value from a drug design point of view.

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