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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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August 30, 2007

Elbow Room

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Posted by Derek

I hope that in decades to come that our current drugs look as crude as I think they will. For all of our knowledge and all our equipment, we still don't have much of an idea of what we're doing around this industry, not compared to the sum of what there is to know.

Most of our drugs (by "most", I mean way over 95%) bind to proteins. And that's fine, as far as it goes, because proteins sure are important things. We love them because many of them have pockets and cavities that fit small molecules, of course, giving us a tremendous leg up. But it's not that we've figured out how to attack them reliably, though, when you consider that there are many entire classes that have never been successfully targeted (phosphatases, to pick an outstanding example).

Once you get out of the small-molecule-binding zone, you're out in the wild, wide open prairie of protein-protein interactions. So far, we can't really affect those with small molecules, not worth squat. It's a shame, because the number of potential targets goes up by orders of magnitude when you take these interactions into account - well, assuming that we figure out what these zillions of interactions are actually doing, which is quite another problem in itself. But they're doing something, that's for sure, and we'd love to be able to step in for our own purposes.

But protein-protein interactions are only the beginning. If you want to go upstream and alter protein production at the source, then you're going to be targeting protein-DNA and protein-RNA) interactions. The list of known drug-like molecules which can do that is pretty short, and the success rate has been pretty small (more on the reasons for that in another post). And this is another area where only small regions of interaction space have been mapped out and understood, so there's room to work in - if you can find a way to make things work.

Don't stop there, though. We really don't pay enough attention to carbohydrates in all their forms, but they've got some crucial roles, too. Contacts involving complex polysaccharides are key to immune function, and small molecules that can affect them are rare indeed. A whole landscape of inflammation targets is waiting for someone who can get a handle on this stuff. And I haven't even talked about lipids, because frankly, we don't understand a lot of what they're doing. Protein-lipid interactions have been targeted, but can be a hard row to hoe, since the small molecules that work tend to look awfully greasy themselves. But there may also be lipid-lipid interactions that no one has ever noticed, and how you'd target those therapeutically is a real stumper.

There are even more exotic combinations, but you get the idea. When you look at the whole medicinally active universe, it's clear that we've only done successful work in a few small parts of it. An interesting and rewarding time awaits those who can extend those holdings. . .

Comments (17) + TrackBacks (0) | Category: Drug Development | Pharma 101


COMMENTS

1. Curious Wavefunction on August 30, 2007 11:36 AM writes...

On reading this post, I just get an exciting feeling up my spine, because it just shows how many amazing opportunities there are out there.

We have to distinguish between rational ligand design and rational drug design. Ligand design essentially is a chemistry problem, while drug design goes much beyond the realm of chemistry.

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2. RKN on August 30, 2007 11:57 AM writes...

Ligand design essentially is a chemistry problem, while drug design goes much beyond the realm of chemistry.

Good point, because Derek mentioned there's no drugs that target phosphatases. But I just plop a pill in 1 mL of water and viola!, I have ten ([10X]!) 100 uL aliquots of broad spectrum phosphatase inhibitor in the freezer sufficient for dozens of experiments.

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3. 7374e9 on August 30, 2007 12:22 PM writes...

The opportunities for exploiting more complex drug action mechanisms are exciting, but we could still get more out of the small-molecule-binding protein drugs if we were able to deliver them to the diseased tissue (asssume we are talking about a disease that is localized like a solid tumor). Imagine what unknown wonders of efficacy we can discover while cutting down on toxicity.

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4. Boghog on August 30, 2007 1:35 PM writes...

Once you get out of the small-molecule-binding zone, you're out in the wild, wide open prairie of protein-protein interactions. So far, we can't really affect those with small molecules, not worth squat.

But we are starting to with large molecules (i.e., biologics).

If you want to go upstream and alter protein production at the source, then you're going to be targeting protein-DNA (and protein-RNA) interactions.

Well in a sense we are already doing that with drugs that target nuclear receptors. The binding sites for these drugs are comprised entirely of protein, but nevertheless these drugs allosterically regulate the binding of their cognate receptors to DNA. On the other hand, there are only 48 nuclear receptors in humans while there are several thousand additional transcription factors that bind to DNA. So there are potentially a lot of opportunities IF selective modulators of these other transcription factors could be developed.

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5. anon on August 30, 2007 2:42 PM writes...

Just echoing curious wavefunction this post is incredibly exciting ...

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6. NJBiologist on August 30, 2007 8:48 PM writes...

RKN:
Good point, because Derek mentioned there's no drugs that target phosphatases. But I just plop a pill in 1 mL of water and viola!, I have ten ([10X]!) 100 uL aliquots of broad spectrum phosphatase inhibitor in the freezer sufficient for dozens of experiments.

--Yes, but those are chemicals, not drugs. Things like orthovanadate will NEVER be drugs, and even if they were, we'd have no idea whether it was a phosphatase mechanism of action.


Derek, Boghog:
Once you get out of the small-molecule-binding zone, you're out in the wild, wide open prairie of protein-protein interactions. So far, we can't really affect those with small molecules, not worth squat.

--Isn't that what taxol (and its congeners) and the vinca alkaloids and colchicine all do?

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7. RKN on August 30, 2007 8:54 PM writes...

--Yes, but those are chemicals, not drugs.

Correct, which was my point, echoing Wavefunction's point that ligands are chemicals and not necessarily drugs. Pardon please if I was unclear.

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8. Malcolm on August 30, 2007 11:03 PM writes...

Looking at this from a different perspective, perhaps it's not that we "can't" affect (e.g. disrupt) these other bits of molecular physiology, it's just that we have a hell of a time understanding those systems in the first place. Perhaps our existing drugs are exerting some part of their action via just such mechanisms.

On the pessimistic side, while ligand-receptor and substrate-enzyme systems are often amenable to a reductionist functional analysis, my impression of the science of protein-protein interactions and transcription factors is that teasing out a chain of cause and effect with arrows up and downstream is very hard indeed. Jamming a spanner in may have effects that are subtle, pervasive and highly unpredictable.

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9. Chrispy on August 31, 2007 1:11 AM writes...


I'll bet that over 5% of drugs are not protein binders, per se.

Consider the gaseous anesthetics -- they bind to membranes or ???? Who knows? All vaccines (well, I guess parts bind to proteins eventually but they are more complex than that). Consider Copaxone, Teva's MS drug which is a polymer of four amino acids and is supposed to "distract" the immune system. (?) That's a blockbuster and a half, by the way. How about thalidomide, with no defined target despite no lack of looking. I'll bet if it bound a protein we'd know what it was! How about hydrogen peroxide and iodine? What about the antifungals? Amphotericin B type antifungals bind ergosterol in the fungal cell membrane.

What worries me in drug discovery today is that people are so mechanism-based and risk averse that they feel they must understand the underpinnings of a compound's action. Many of the best drugs are dirty -- think about all the targets aspririn hits. We've got this selectivity myopia which is not allowing us to ask they bigger question of how small molecules affect entire systems. Even when we release dirty drugs we have the nerve to call them things like selective serotinin reuptake inhibitors (note to docs: the best ones are the dirtiest). The only exception I know is kinases, where multi-kinase inhibitors are coming to the fore probably in part because they've proven efficacious. And maybe because selectivity is really very hard, especially with kinases.

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10. Boghog on August 31, 2007 2:48 AM writes...

@NJBiologist
Isn't that what taxol (and its congeners) and the vinca alkaloids and colchicine all do?

Good point. And to the tubulin example you cite, one could also add nuclear receptors. NR ligands both disrupt (NR/heat shock protein) and promote (NR dimerization) protein-protein interactions. However both of the tubulin and NR examples are special cases. There is no general strategy for controlling protein-protein interactions with small molecules.

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11. befuddled on August 31, 2007 7:29 AM writes...

Derek,
Is the lack of successful phosphatase inhibitors due to a lack of leads, or to the side effects of the compounds?

Chrispy,
We can add polymyxin B, which binds lipopolysaccharide (of course, we humans didn't make it; fungi did). And I'm sure that many of the peptide-synthesis inhibiting antibiotics (thiostrepton, streptomycin) have binding sites composed at least in part of RNA.

So it's doable, just hard.

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12. MolecularGeek on August 31, 2007 9:12 AM writes...

Consider the gaseous anesthetics -- they bind to membranes or ???? Who knows?

Actually, the current thinking in the field is that most of the inhalation anesthetics are active by modulation of the GABA-a and glycine receptors. Nitrous oxide and Xenon, however seem to act at NMDA receptors and beta nAChr subunits. That classic QSAR where activity is tied solely to log(P) is probably just reflecting transport properties.

MG

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13. SynChem on August 31, 2007 9:28 AM writes...

"What worries me in drug discovery today is that people are so mechanism-based and risk averse that they feel they must understand the underpinnings of a compound's action. "--Chrispy

I guess blame that on the "rational drug design" approach that emerged several decades ago. Relying on serendepity can only go so far. And the "irratiojnal" approach is, well, irrational and unpredictable. But again, we're baffled most of the times anyway. What's a little more hand-waving gonna hurt.

And most importantly, "rational design" gives us medicinal chemists our jobs and makes us feel important. Take that away, even fewer people would want to go through chemistry grad school. :)

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14. MTK on August 31, 2007 10:45 AM writes...

"What worries me in drug discovery today is that people are so mechanism-based and risk averse that they feel they must understand the underpinnings of a compound's action. "--Chrispy

"I guess blame that on the "rational drug design" approach that emerged several decades ago. Relying on serendepity can only go so far. And the "irratiojnal" approach is, well, irrational and unpredictable. But again, we're baffled most of the times anyway. What's a little more hand-waving gonna hurt"--SynChem

Well, there is another reason and that's regulatory concerns. It's pretty darn tough to have an IND go through without questions much less get FDA approval with a PD section that says "We're not sure." The FDA wants to know that you have some ideas at least of what's going on or what should go on, so that the appropriate clinical and safety studies are run.

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15. Anonymous BMS Researcher on August 31, 2007 12:47 PM writes...

Aspirin, yep, I've often mentioned that one myself as an example of something we'd be loath to give up now but it's hard to imagine getting very far in our current environment! And the stuff was in commercial use for about a hundred years (or thousands of years if you count the traditional use of natural salicylates before pure aspirin was made) before we knew some of its most valuable uses!

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16. Fries with that? on August 31, 2007 8:36 PM writes...

Are all protein protein interactions off the table in terms of drug discovery? I know chemists laugh themselves silly at some of the ideas we biologists have for disrupting interactions in a cell, but if there is a decent hydrophobic pocket and something to grab onto within it, is there a chance of finding a small molecule that will latch on?

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17. kiwi on September 1, 2007 4:34 AM writes...

"... but if there is a decent hydrophobic pocket and something to grab onto within it, is there a chance of finding a small molecule that will latch on?"

Sure, it is possible to eventually get your hands on a molecule that will bind to that cleft, but an analogy would be trying to stop two elephants touching, by taping a grain of rice to one them.

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