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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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August 14, 2007

Winning, By Tying Losers Together

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Posted by Derek

A co-worker put me on to an interesting paper earlier this year by Harvard's George Whitesides (with a co-author credit going to a well-known chem-blogger). Whitesides, a perennial favorite in Nobel betting, does a lot of absolutely first-tier physical organic chemistry, an area that I love to read about (and one that I'd probably be an awful practitioner of).

Almost all drugs bind to sites on proteins. Some proteins have only one site (that we know of) that a small molecule will fit into, while others have several. There have been a lot of attempts over the years to go after the latter group by hitting more than one site at the same time - but with only one drug. Imagine two different drug molecules, each fitting into a different site on a single (multi-sited) protein. Now imagine combining them into one compound, by attaching some sort of linking chain between them, and you've got one (larger) molecule that can reach around and fill two binding sites.

This has worked in some cases, at least on a research level (I'm not aware of any drugs that have yet made it to market by taking advantage of this effect, though). (Update: there is a marketed protein, bivalirudin, that binds to two sites on thrombin, but I'm still not aware of any small molecule drugs in this category). You can pick up huge amounts of affinity by this trick, though, to the point that neither of the original "business ends" of the molecule need to be particularly good binders on their own. And since we in the industry are distressingly good at producing molecules that don't bind to things very well, the idea of combining some of these into multivalent wonders is appealing.

But there are a lot of unknowns. Figuring out how to modify the original structures in order to tie them together is, as they say, non-trivial. (If you hang around scientists and engineers much, you know to head for cover when you hear that expression). And what kind of chain should you use, anyway? How long does it have to be, and what happens if it's too long or too short? And what's the linking chain doing, anyway - sticking to the surface of the protein, waving around by itself, or what?

Whitesides and his people have used carbonic anhydrase as a model system, which is an enzyme whose structure and behavior is as well known as these things get. They find, not unreasonably, that when the linking chain is too short the activity of your wonder molecule just gets killed: you're stuck with one end bound to the protein, and a big tail flopping around uselessly, unable to reach the next binding site. The "just-right" chain length is the best, naturally. But (interestingly) you don't pay much of a penalty for being longer than necessary, even several times longer. Apparently the chain will coil around and find something to do with itself as long as the two ends are bound.

And while it's doing this, it doesn't appear to be contacting the protein in any meaningful way. This took a lot of careful experimental thermodynamics to check, but there's no extra binding energy involved with any of the common chains. So if you're going to try this trick, Whitesides's advice is not to worry about what chain to use. Stick with a plain-vanilla linker, as flexible as possible, make it a bit longer (at least at first) than you think you'll need, and you've improved your chances right there. And he has the numbers to back this up, which is what physical organic chemistry is all about: opinions made solid by data. It's good stuff.

Comments (29) + TrackBacks (0) | Category: Drug Development | General Scientific News


1. Matt on August 14, 2007 9:28 PM writes...

I think there is a drug that was designed like this...I think it was mentioned in one of my biochem classes, I just can remember what it is right now. If I remember I'll definitely post it.

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2. xchemist on August 14, 2007 11:09 PM writes...

Check out bivalirudin (Angiomax, hirgulog), discovered at Biogen, licensed and commercialized by The Medicines Company as an antithrombotic. Binds both to thrombin's active site and an enzyme surface (exosite) anion binding site. Some very interesting IP associated with the compound as well, see US Patent No. 5,196,404.

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3. Grad on August 14, 2007 11:23 PM writes...

eh, Whitesides is massively overrated. And he's a prick in person too.

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4. DLIB on August 15, 2007 1:02 AM writes...

Are you suggesting that Medicinal Chemists may gleen useful information and guidance from Thermodynamics? I've yet met one who thinks it's a "must have". Mostly pictures/Kd/Kon/Koff almost never dH or dS or dCp. At least from the ones I've met.

This is one of the massive gaps that Pharma needs to breach.

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5. milksahake on August 15, 2007 6:40 AM writes...

I am sceptical about the value of this publication.

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6. MTK on August 15, 2007 7:27 AM writes...

I haven't read the Whitesides paper, but this would obviously be the type of thing that anyone involved in fragment-based drug discovery would be interested in, specifically if they are using fragment-linking approaches.

The other area in which this type of research might be interesting is glycomics. In general carbohydrate-protein binding is quite weak, in the mM - microM range, which means that nearly all carbohydrate recognition is multivalent. For those who don't know a huge number of pathogen related interactions proceed through multivalent carbohydrate binding, so understanding or developing probes for such studies is very interesting.

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7. weirdo on August 15, 2007 10:04 AM writes...

Wasn't this the whole super-secret concept behind Advanced Medicines "fully enabling proprietary drug discovery technology".

Sorry, I think they've been renamed Vernalis now, "to more accurately reflect their primary mission".

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8. WC on August 15, 2007 10:20 AM writes...

Weirdo, you're correct, Advanced Medicine started with this multivalency concept for drug discovery. They are now called Theravance and I think Whitesides was one of the founders (I might be thinking of a different company).

I interviewed a candidate recently who had done this "multivalency" approach to drug discovery and IMO it was very time consuming and many analogs were made to get to the optimum compounds. It's interesting stuff, but I'd have a hard time saying it's efficient, at least from the example I saw.

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9. Anonymous on August 15, 2007 10:31 AM writes...

Its all crap in my opinion!

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10. Darth Bubbster on August 15, 2007 10:42 AM writes...

As a long-ago member of the SAR-by-NMR team at Abbott, I can guarantee you that doing this (successfully) is harder than anyone makes it sound.

Sure, you can find things that bind to two sites -- but linking them together rarely gets you the increase in Kd that you think it ought to. Oh, and big long floppy linkers are wonderful for improving "drug-like" properties.

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11. MTK on August 15, 2007 11:24 AM writes...

Interesting to know Darth considering how fragment based discovery is all the rage.

For anyone who'd like to know a little more decent, but now somewhat dated review is Rees et al, Nature Reviews Drug Discovery, 2004, 3, 660. It provides a nice overview of approaches within the field along with some tables of examples of leads that were ID'ed using a the various methods described.

Within that review they make mention of computational studies that suggest that by linking two fragments together a "super-additive" effect could be realized. Darth's comment would seem to indicate that in reality that is not observed.

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12. goldilocks on August 15, 2007 11:52 AM writes...

Weren't both Sunesis and Astex founded on this type of work? Or am I missing something?

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13. Hap on August 15, 2007 12:20 PM writes...

A previous publication by Prof. whitesides (JACS 128(2007), p. 5802) seems to indicate that selecting effective ligands with secondary binding sites is nontrivial - that finding a good secondary weak binding site might not help you get a better binding ligand, because the loss of entropy might outweigh the added binding enthalpy (at least that's what I got from it). Ihadn't seen this paper though, and quantifying the effects might mean that multivalent binding wouldn't be as hard to implement as the first paper makes it seem.

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14. spook on August 15, 2007 1:13 PM writes...

Theravance is a Whitesides venture; people from Whitesides' lab are in charge of the science there. Theravance's linker technology is based on Whitesides' research. Theravance calls it "multi-valency". They have launched one antibiotic, Telavancim, but it is not a proof of concept molecule. Their 2nd generation anti-biotic (TD-1792) is however. There clinical products for COPD/asthma are multi-valent.

Roy Vagelos (former CEO of Merck) has been chairman of the board since the inception of Theravance so he is a big believer in Whitesides' ideas.

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15. spook on August 15, 2007 1:16 PM writes...

oops...bad grammar. I meant to say "their" and not there

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16. Wavefunction on August 15, 2007 2:22 PM writes...

This basically seems to be a vindication of what Whitesides has been saying for a long time, that entropy in prot-lig binding has been neglected. For example, see:
Quarterly Reviews of Biophysics 38, 4 (2005), pp. 385–395

I think this is good and careful work, although similar to his entropy-enthalpy compensation paper published a year ago with Krishnamurthy. The general hypothesis is not too surprising, that the best EM would result from an optimum linker length, but it's always nice to have a careful study of a system to cite. Let's not also forget that Ron Breslow had talked about the "chelate effect" a long time ago.
Pure Appl. Chem., Vol. 72, No. 3, pp. 333–342, 2000

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17. xchemist on August 16, 2007 1:27 AM writes...

Just to restate my earlier point about bivalirudin, this is a very old concept. See for instance:

But it seems to me that at some level many or most or maybe all current drugs (lithium aside) work by a variant of the idea that small positive binding contributions, linked together, turn into big ones. That's the idea, of couse, behind multi-point pharmacophores, although the linker isn't highly flexible in many cases.

Ion channel blockers are a good example of this idea. Take a look, for instance, at the structure of verapamil, a couple of grease balls and a positive charge held together with carbon chains. In its day it sold gazillions of dollars.

And what does one make of a compound like aripiprazole, a current >billion dollar-selling drug? How much does the butyloxy chain in the middle of the molecule add to binding affinity? I'm guessing not precious much aside from positioning the arylpiperazine and tetrahydroquinolinone groups.

Great post by the way, Derek, one of many examples of "what goes around comes around".

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18. DrSnowboard on August 16, 2007 2:46 AM writes...

Hey, didn't GSK believe it enough to buy the option to license the Theravance farm. Kerching..
And to complete the circle I think the first post is thinking of the anchored agonist argument for the LABA activity of salmeterol.

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19. John Spevacek on August 16, 2007 7:57 AM writes...

I'm reminded of polymer crystallization. The chains of flexible polymers do not crystallize in an extended form ("spaghetti in a box"), but instead fold back and forth. The folds at the ends come in many forms: adjacent re-entry and non adjacent re-entry with large and small loops are all possible, none of which prevent the crystallization for proceeding.

If a protein folds in milliseconds, the free end of a semibound molecule should have no problem exploring the physical space in a short period of time.

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20. SynChem on August 16, 2007 8:43 AM writes...

The underlining principal is the same as the fragment based approach. It's a nice extention/application of the concept but I believe of little real-world significance. It's hard to imagine a molecule like that will be drug-like, which people in academia tend to so easily ignore.

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21. Mike on August 16, 2007 11:40 AM writes...

Does Derek ever have any intention of commenting on anything relevent to Chemists today? I took a look at this thing and it's all just fluff and dribble.

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22. eugene on August 16, 2007 12:05 PM writes...

Wow, that's a good idea Mike. I mean, we pay our hard earned money to Derek so that he can write his little blog here, and we got totally shafted. I know that everyday I'm forced to read this blog since I write Derek a check for a cool $20 every month, and every single day I say to myself: "Man, why isn't there anything relevent (sic) to Chemists today here!?"

Where is the stuff about people losing their jobs due to downsizing or pharma companies shutting down research sites and then being out of work for months on end? Where is the commentary on the nature of pharma, drug discovery, and the future of total synthesis? Not here, that's for sure!

Come on Derek, enough with the fluff and dribble. Get with the program and write about stuff that is relevent (sic) to Chemists today or stop forcing me to read your blog!

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23. fries with that? on August 16, 2007 4:47 PM writes...

Drug discovery is hard. Fragment screening is currently the darling of the buzzword crowd, running a close second to RNAi.
Every lecture or review article on fragment screening starts with the mandatory bashing of that lowly, backwards HTS. HTS is for wallflowers, fragment screening is for the beautiful people.
The one thing missing, though, are any real metrics that compare the two methods head to head.
The real truth is that fragment based methods are likely no more efficient that any other method used for the discovery of new therapeutics, including wretched, wicked HTS.

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24. Jose on August 16, 2007 5:28 PM writes...

Derek- any thoughts on AMGN, aside from the obvious concern for employees?

This guy should be given a blindfold and a last cigarette-

"It doesn't look like they're cutting muscle or brawn, but trimming the fat around the edges," said Geoffrey Porges, an analyst with Sanford C. Bernstein in New York, in an interview with Bloomberg News. "It's encouraging because it shows the company is committed to preserving earnings, cash flow and shareholder value."

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25. Polymer Bound on August 16, 2007 6:32 PM writes...

Fragment based approaches work well in the presence of structural information... on its own, there's a low probability of success. Abbot has published some of their metrics on this, although I don't know if a vigorous comparison to HTS was made. My understanding is that Abbot generally applies fragment screening when HTS fails to provide tractable leads.

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26. SRC on August 18, 2007 1:26 PM writes...

As pointed above, this approach is simply the chelate effect writ large. And it predates Breslow by the better part of a century, with the realization that ethylenediamine is a much better ligand than two ammonia molecules. It's been a staple of undergraduate inorganic chemistry courses for generations now.

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27. Ogan Gurel on August 23, 2007 8:44 PM writes...

Entropy in protein-ligand binding is overrated.

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28. Vijay Krishnamurthy on October 26, 2007 5:34 PM writes...

Hi Derek,

I have been a big fan of your blog and was pleasantly surprised to see your discussion of our recent paper while browsing the archives. You perfectly captured the key point that the affinity of the ligand was remarkably independent of linker length. We certainly hope that these results can be of use in the design of multivalent ligands to other proteins of greater therapeutic interest, in industry (as well as academia).

Jahnke and Erlanson recently co-edited a book--"Fragment-based Approaches to Drug Discovery"--that contains a number of seminal reviews about the concept of tethering. A number of the examples discussed are from industry and might be of interest to this audience. (For full disclosure, we contributed a chapter on multivalency).

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29. Vijay Krishnamurthy on October 26, 2007 5:45 PM writes...

Also, to address previous posters (e.g., #26), who said that multivalency is "simply the chelate effect writ large." Indeed, there are many parallels, but things become remarkably more complicated when a protein is involved (e.g., how do you think about linker-protein contacts, which are not a factor when looking at simple metal-ligand chelation).

Even in the simple case of metal-ligand chelation, the big question remains of how much tighter should two (or more) molecules/ligands linked together bind to a protein than should those same two molecules not linked? The answer involves the translational+rotational entropy of the species, conformational entropy, solvation effects, etc. (not to mention protein contacts). So, certainly not a simple thermodynamic calculation! But, one that we must address to use multivalency effectively.

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