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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: Twitter: Dereklowe

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October 23, 2013

Allosteric Binding Illuminated?

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Posted by Derek

G-protein coupled receptors are one of those areas that I used to think I understood, until I understood them better. These things are very far from being on/off light switches mounted in drywall - they have a lot of different signaling mechanisms, and none of them are simple, either.

One of those that's been known for a long time, but remains quite murky, is allosteric modulation. There are many compounds known that clearly are not binding at the actual ligand site in some types of GPCR, but (equally clearly) can affect their signaling by binding to them somewhere else. So receptors have allosteric sites - but what do they do? And what ligands naturally bind to them (if any)? And by what mechanism does that binding modulate the downstream signaling, and are there effects that we can take advantage of as medicinal chemists? Open questions, all of them.

There's a new paper in Nature that tries to make sense of this, and trying by what might be the most difficult way possible: through computational modeling. Not all that long ago, this might well have been a fool's errand. But we're learning a lot about the details of GPCR structure from the recent X-ray work, and we're also able to handle a lot more computational load than we used to. That's particularly true if we are David Shaw and the D. E. Shaw company, part of the not-all-that-roomy Venn diagram intersection of quantitative Wall Street traders and computational chemists. Shaw has the resources to put together some serious hardware and software, and a team of people to make sure that the processing units get frequent exercise.
They're looking at the muscarinic M2 receptor, an old friend of mine for which I produced I-know-not-how-many antagonist candidates about twenty years ago. The allosteric region is up near the surface of the receptor, about 15A from the acetylcholine binding site, and it looks like all the compounds that bind up there do so via cation/pi interactions with aromatic residues in the protein. (That holds true for compounds as diverse as gallamine, alcuronium, and strychnine), and the one shown in the figure. This is very much in line with SAR and mutagenesis results over the years, but there are some key differences. Many people had thought that the aromatic groups of the ligands the receptors must have been interacting, but this doesn't seem to be the case. There also don't seem to be any interactions between the positively charged parts of the ligands and anionic residues on nearby loops of the protein (which is a rationale I remember from my days in the muscarinic field).

The simulations suggest that the two sites are very much in communication with each other. The width and conformation of the extracellular vestibule space can change according to what allosteric ligand occupies it, and this affects whether the effect on regular ligand binding is positive or negative, and to what degree. There can also, in some cases, be direct electrostatic interactions between the two ligands, for the larger allosteric compounds. I was very glad to see that the Shaw group's simulations suggested some experiments: one set with modified ligands, which would be predicted to affect the receptor in defined ways, and another set with point mutations in the receptor, which would be predicted to change the activities of the known ligands. These experiments were carried out by co-authors at Monash University in Australia, and (gratifyingly) seem to confirm the model. Too many computational papers (and to be fair, too many non-computational papers) don't get quite to the "We made some predictions and put our ideas to the test" stage, and I'm glad this one does.

Comments (14) + TrackBacks (0) | Category: Biological News | In Silico | The Central Nervous System


1. Krishna on October 23, 2013 5:37 PM writes...

It is very impressive the scale of molecular dynamics simulations that they were able to run in these experiments. But, I am not too sure if this allosteric site theory can be generalized for all gpcrs or even to a different class of allosteric modulators of muscarinic receptors. The authors themselves suggested that several mutagenesis studies have provided evidence of the presence of other allosteric binding sites along the transmembrane helices and the intracellular loops. Still very interesting and a long way to go.

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2. Krishna on October 23, 2013 5:38 PM writes...

It is very impressive the scale of molecular dynamics simulations that they were able to run in these experiments. But, I am not too sure if this allosteric site theory can be generalized for all gpcrs or even to a different class of allosteric modulators of muscarinic receptors. The authors themselves suggested that several mutagenesis studies have provided evidence of the presence of other allosteric binding sites along the transmembrane helices and the intracellular loops. Still very interesting and a long way to go.

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3. PharmaHeretic on October 23, 2013 5:54 PM writes...

I have a feeling that this new comment system has the potential for providing considerable public entertainment. So let the inevitable flame-wars and trolling begin.

"At 11 AM on October 22, 2013, the embargo was lifted and so now it can be said: PubMed Commons has been implemented on a trial basis. It could change the process of peer assessment of scientific articles forever. Some researchers can now comment on any article indexed at PubMed and read the comments of others."

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4. Anonymous on October 23, 2013 10:38 PM writes...

Validation of most computational studies are not done, not because the computational guys don't want them done.

There's very little incentive to validate computational predictions in terms of ROI . And where an incentive exists, domain experts don't wanna do it fearing redundancy and a sense of hubris.

Notice that the (well funded) Shaw group did not invest in doing the wet lab validation, rather their collaborators did. Wonder why :-)

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5. cdsouthan on October 24, 2013 3:01 AM writes...

4 touches on a key point and widespread problem as more CPU power and expanding databases make in silico experiments so much cheaper that tough and messy med chem, enzymology and receptor pharmacolgy.

OK; so from now on any of the 1000s of Pipeline readers who get comp chem or VS papers to reveiew that could obviosly be supported by experiments, they should insist on this (even if the authors have to pay a CRO to do the assys). If that's a no-go we can now (politely) point this out in PubMed Commons.

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6. donovan on October 24, 2013 7:55 AM writes...

@5... Where do you think smaller academic labs will get the money to hire these CROs? Or should all medchem research come from super-groups like Shaw?

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7. CCguy on October 24, 2013 8:28 AM writes...

@4, If that's what happens in your organization, more fool you. Where I work the only reason I still have a job is because someone still thinks my predictions are worth testing. Then again, maybe that's because I don't believe in massive simulations.

If you meant to say that validation of published academic modeling studies isn't usually done, I agree, and when it does get done it's done badly. I reject those myself when I get to review them and I wish everyone else would too.

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8. Curious Wavefunction on October 24, 2013 9:34 AM writes...

#4 is absolutely right. The kind of basic, painstaking studies (like measuring solvation energies and dipole moments for simple molecules) that need to be done to validate computational techniques are considered unfashionable and boring by the NIH, in spite of the fact that they are cheap and have a direct impact on simulating more complex systems like proteins. Sadly this is emblematic of an age where glamorous research is pursued at the cost of more mundane but important work.

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9. a. nonymaus on October 24, 2013 9:52 AM writes...

Re: 4
Also, occasionally one's experimental collaborators will decide to publish on their own and scoop the computationalists. A colleague had this happen to them.

Re: 8
There are a few experimental groups still doing fundamental phys-org studies on small molecules. See, for instance, what John Roberts at Caltech has been doing in recent decades with NMR studies on conformational preferences of molecules in solution. These results include charge-charge, charge-dipole, cation-pi, steric, hydrogen-bonding, et c., et c., interactions in non-polar, polar, and protic (H and D, even) solvents. If computationalists can get predictions of gauche-trans ratios for these small molecules that match the gamut of the experimental data, it would probably quell a lot of the nay-saying. I, for one, would welcome a paper that does this kind of validation. Ladies and Gentlemen, start your analytical engines.

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10. Curious Wavefunction on October 24, 2013 10:43 AM writes...

#9: Yes, I agree that John Roberts's work is a great example of the kinds of studies that should stimulate validation of computational techniques. But the man is 95. We need a new breed of chemists to pick up the baton and run with it. Measurements of the kind Roberts does seem to have virtually disappeared with the death of "classical" physical organic chemistry, at least some parts of which deserve to be dug up from the grave.

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11. Pennpenn on October 24, 2013 5:25 PM writes...

"I used to think I understood, until I understood (it) better"

I wonder if there is a Latin translation- it'd make a great motto for science...

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12. Anonymous on October 25, 2013 8:40 AM writes...


"Ego puto intelligi intelligantur donec," as per Google Translate ("I used to think I understand, until I understood better"). Not catchy, but I agree it is at least a good candidate for a motto. Along with "Back off. I'm a scientist."

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13. Crimso on October 25, 2013 8:42 AM writes...

#12 was me. Forgot to fill out the fields. Thought I understood how this blog commenting thing works...

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14. Rich Guy on November 16, 2013 2:56 AM writes...

Seriously, DEShaw bought another Science paper? This is a mockery of science. Did he buy the reviewers too? Or just the whole journal?

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