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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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« Tribes | Main | The Hazards of Molecular Modeling »

September 28, 2005

Clamping Down, or Loosening Up?

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Posted by Derek

We medicinal chemists spend our days trying to make small molecules that bind to targets in living systems. Almost all of those targets are proteins of one sort or another, and most of them have binding pockets already built into them, which we're trying to hijack for our own purposes. Molecular modelers try to figure out how these things fit together, but there are still a lot of unknowns in what would seem so basic a process.

I'm willing to bet that most chemists and biologists have a mental picture of a small molecule ligand fitting into a binding site which involves the protein sort of folding down around things - gently biting down on the ligand, as it were. It seems intuitively obvious that a protein's motions would settle down once it complexes with its target molecule.

And like a lot of intuitively obvious things in drug research, that idea appears to be mistaken. There's a recent study in the Journal of Medicinal Chemistry from a group at Michigan that tackles this question in a rigorous manner. They looked through the X-ray crystal structure data banks for proteins that have had high-quality structures determined both with and without small molecules bound in them. After controlling for experimental conditions (the temperature that the X-ray structure was taken at, among other things) and for the way the data were processed, they still had a few dozen closely matched pairs.

What they found was that in most of these structures, at least some of the atoms in and near the binding site are more mobile when there's a ligand bound. At times, the effect was pretty dramatic, with the entire binding site becoming more flexible, weirdly enough. Examples where everything got less mobile were found, but that only happened in a minority of the cases. The proteins the authors studied were scattered across a wide range of structural and functional classes, and there's no reason to think that they hit on an anomalous data set.

So, we're going to have to adjust our mental pictures, and the molecular modelers will have to adjust their simulations. I'd like to know just how many of those in silico models of binding would have predicted this greater flexibility. I fear that the answer is "darn near none of them". We have a long way to go.

Comments (9) + TrackBacks (0) | Category: In Silico


1. The Novice Chemist on September 28, 2005 9:21 PM writes...

Has anyone looked at real-time methods for watching molecules bind to their targets? Dynamic NMR, for example? I'm sure it would be hard to deconvolute everything, but you'd think it could be done.

You'd figure (I'm being naive here) that you'd just throw some enzyme into a NMR tube, run the NMR and then throw the inhibitor in and see what changes. I'm sure there's a reason why this is improbable or impractical.

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2. UndergradChemist on September 28, 2005 9:51 PM writes...

This reminds me of an idea that I once heard in p-chem class. The tighter a molecule binds, the more entropic cost it has, and in simple models, this can offset the enthalpic gain of binding. The data was pretty interesting, as there was a definite correlation between enthalpy and entropy of the system. One of the ideas that was proposed was that to bind "better," an alternative strategy to looking for better or more bonds would be that one could look for entropic gain instead.

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3. milo on September 28, 2005 10:52 PM writes...


Checkout some of the literature on cooperative interactions. Turns out that in some cases, increased binding is infact do to entropic considerations. I think some of J. Rebek's early work shows that. I would know for sure if my thesis was handy...

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4. SRC on September 28, 2005 11:11 PM writes...

I haven't read the article, and don't have time to right now, but I trust they took disorder/partial occupancy (i.e., crystallographic artifacts) into account.

Their observations (as reported here) are consistent with partial occupancy of the binding site, on either a time or ensemble basis, which would yield exactly what they reported. (Strong binding and rapid kinetics are, of course, not mutually exclusive, and the timescale of X-ray is geologic by molecular standards.)

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5. qetzal on September 28, 2005 11:22 PM writes...

Re binding based on entropic gains. IIRC, that applies in at least some cases of ligands that bind DNA. A large number of individual water molecules that cluster around the negatively charged backbone (so-called waters of hydration) get replaced with a single ligand. Additional waters of hydration may also get displaced from the binding surface of the ligand (which, naturally enough, tends to be positively charged).

The net effect is a large entropic contribution to binding energy, which can be the dominant term, maybe even overcoming an unfavorable enthalpy.

OTOH, I could be remembering this all wrong - it's been quite a while....

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6. Derek Lowe on September 29, 2005 9:10 AM writes...

As for NMR studies, this may have been seen, but in an uninterpretable way. From what I've seen of NMR binding studies, many changes are noted in chemical shift, relaxation times, peak width, and so on, but it can be hard to figure out what caused them.

If the Michigan paper is correct (and it looks pretty well thought-out), then some of the changes will have been due to direct interaction with the ligand (and presumably more restricted movement), and some of them will turn out to be from increased mobility.

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7. milo on September 29, 2005 12:32 PM writes...

If anything, this serves as a reminder that nature is a lot more complex than we normally give it credit for. I like to think of modelling as the "silent killer". It is easy to rely on it for quick answers, and easy to forget that there is no substitute for an actual experiment.

I can generate a pseudo 3d structure and "see" the binding pocket. Using this I can envision putting a methyl here, a carbonyl there, maybe that would increase binding... I can even get a number (in kcal/mol!) from the software. In the end though, I need to make that darn thing to see if it actually inhibits the enzyme.

I remember asking a fellow scientist if a particular molecule performed as hypothesized, the response was: " I don't know. It did not dock well into the enzyme, so I didn't make it."

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8. Complex Guy on September 30, 2005 7:45 PM writes...

I think SRC is possibly on to something. Incomplete occupancy of sites would certainly give rise to what looked like "dynamics" in the binding site. It would also be interesting to know if they binned their structures into 2 flavors - genuine co-crystals and crystals that were soaked with ligands (the more common approach). This is especially relevant for the free-bound comparison that was so critical to their paper. The soaking might not provide complete occupancy and/or cause heterogeniety in the binding site due to 2 or more mechanisms for adaptation of the protein structure upon binding.

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9. tgibbs on October 1, 2005 5:47 PM writes...

Consider a receptor with a flexible chain, which is tacked down by binding to another site on the receptor. A ligand competes for the binding site, freeing the chain to wave in the breeze.

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