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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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March 20, 2014

Small Molecule Chemistry's "Limited Utility"?

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Posted by Derek

Over at LifeSciVC, guest blogger Jonathan Montagu talks about small molecules in drug discovery, and how we might move beyond them. Many of the themes he hits have come up around here, understandably - figuring why (and how) some huge molecules manage to have good PK properties, exploiting "natural-product-like" chemical space (again, if we can figure out a good way to do that), working with unusual mechanisms (allosteric sites, covalent inhibitors and probes), and so on. Well worth a read, even if he's more sanguine about structure-based drug discovery than I am. Most people are, come to think of it.

His take is very similar to what I've been telling people in my "state of drug discovery" presentations (at Illinois, most recently) - that we medicinal chemists need to stretch our definitions and move into biomolecule/small molecule hybrids and the like. These things need the techniques of organic chemistry, and we should be the people supplying them. Montagu goes even further than I do, saying that ". . .I believe that small molecule chemistry, as traditionally defined and practiced, has limited utility in today’s world." That may or may not be correct at the moment, but I'm willing to bet that it's going to become more and more correct in the future. We should plan accordingly.

Comments (31) + TrackBacks (0) | Category: Chemical Biology | Chemical News | Drug Development | Drug Industry History


COMMENTS

1. Anonymous on March 20, 2014 11:37 AM writes...

Why do you feel that small molecule chemistry will have a limited role in the future? This is a statement that requires support, as many small molecules continue to be approved for a vast number of indications.

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2. weirdo on March 20, 2014 11:43 AM writes...

This is a very interesting commentary from an individual associated with Nimbus. Take a look at some of their patent applications and try to correlate the structures therein with Montagu's views.

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3. Anonymous on March 20, 2014 11:57 AM writes...

I echo #1.

This is pure sillyness.

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4. Anonymous on March 20, 2014 12:19 PM writes...

@1,3: It's a simple question of energetics: Most small molecules don't have the surface area to effectively and selectively compete with protein-protein interactions. And that's where the future lies, because most of the "small pockets" (ion channels, receptors, active sites) which are available to small molecules have been tapped already.

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5. Curious Wavefunction on March 20, 2014 12:25 PM writes...

#4: As someone who helps design large macrocycle drugs to inhibit PPIs I agree with you. Nonetheless, the rise of biologics, while promising, is exaggerated (click on my handle).

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6. dave w on March 20, 2014 12:29 PM writes...

Perhaps it would be fairer to speak of "large-molecule chemistry's emerging (potential) utility".

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7. patentgeek on March 20, 2014 12:49 PM writes...

"biomolecule/small molecule hybrids"

Antibody-drug conjugates are one example of this. The recent work of Niewoehner et al (Neuron 2014) suggests mAbs may be used to deliver cargo into the CNS, extending the hybrid approach.

The conceptual boundaries between molecules made by synthetic organic chemistry (not necessarily small - see Halaven) and those considered "biomolecules" are becoming blurred, and will continue to blur further in the foreseeable future. Bring it on.

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8. Anonymous on March 20, 2014 1:00 PM writes...

So does this fly in the face of the many posts that claim total synthesis studies are 'worthless'?

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9. Anonymous on March 20, 2014 1:18 PM writes...

@5: The arguments in your linked blog are bunk:

1. The price of biologics is much higher because they are more effective, and save more costs. That's the only reason why payers and providers would be prepared to pay more for them. Cost of goods has nothing to do with price.

2. Yes, antibodies have been most successful against cancer, but that doesn't mean they and other biotherapeutics couldn't be effective or economical against chronic diseases. Again, if they save healthcare costs in the long run by reducing hospitalisation or full-time care, then why not?

3. Yes, large biomolecules have their delivery and PK issues, but many groups are developing different technologies to address this issue, and there is no theoretical reason or limit why this can't be done. Unlike small molecules, which are ultimately limited by their surface area.

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10. annon too on March 20, 2014 1:21 PM writes...

Agree with Derek on the idea that the traditional function of and opportunities for small molecules is in decline and that their perspectives need to change.

Saying that, though, is a bit like saying the train needs to leave the station after it has already arrived at the destination, eg, the need to change has been there for years, and is becoming increasingly necessarily & critical for the "discipline" of Medicinal Chemistry to halt it's decline in jobs etc. At some point, with another "name" of "experts" will take the jobs as "Macromolecular Scientist".

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11. Anon anon anon on March 20, 2014 1:26 PM writes...

Derek: I'd be interested to hear more about your concerns about structure-based drug discovery. I thought you were a fan of fragment-based, for example, and much of the work I've seen for fragments gets developed with structural information.

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12. Anonymous on March 20, 2014 1:31 PM writes...

#11 Derek isn't a fan of anything that involves 'predicting' and 'designing' for improved biological activity. SBDD and QSAR are of no use to him.

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13. Anonymous on March 20, 2014 1:42 PM writes...

@12: And that's because he has enough experience to know that there are no simple, reliable rules or other shortcuts in drug discovery to avoid doing real experiments. Good for him!

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14. Anonymous on March 20, 2014 2:18 PM writes...

Biomolecules have much harder problems to control, such as post translational modifications. Everyone knows how antibodies are significantly influenced by a PTM like glycosylation which you simply can not control. Furthermore, a PTM has PTMs on top of it such as sulfation, acetylation, and phosphorylation which can also alter biological activity. There are examples of biomolecules like mABs that work, but let's not overstate how well we think we can develop these things.

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15. NoDrugsNoJobs on March 20, 2014 6:58 PM writes...

Presently, the favorable economics of large molecules (eg biologicl antibodies) are impossible to ignore. They have a considerbly higer sucess rate in the clinic and are even enouraged by our own biologicals legislation where they get a nice 12 year period of exclsuvity compared o 5 uears for small molecules in the US. They are often quite selective compared to their small moleule brethren and have the capacity to knock in or knock out the protein of interest. However, they are not ging to solve the probems of this planet of approximately 7 billion people when the vast majority could never afford their routine costs, the generally complex and typically refrigerated supply chain, the requireent of sterile needles, etc. its not that small moleules are necessarily cheaper to the consumer initilly where a highly effective drug for a costly disease will be priced acordingly (like the new HepC regimens which will run up to 100 k per treatment but will eradicate this disease entirelt, eventually) but once they go generic, they are forever generic and can be taken with no more thatn a little bit of water to wash them down. The trend towards increased bilogical spends relative to small molecules spends on research makes much short term business sense but less for the long term. I agree wholeheartedly with the concept of developing the special synthetic skills whereby these complex molecules can be modified chemically to convert them to santibody drug conjugstes will get to be a bigger and bigger area of research will no doubt continue for a long time. There are so many additional possibilities that wear only scratching the surface. Having said that, looking at the tremendous success on both big and small molecules makes me so optimistic aboout the futre of pharma research. Just looking at all of the major coups that have been rather quietly accumlating over th past couple of decades is something we can all take very much hope and dare I sat pride for what our industry has accomplished. I've seen so many movies abouth HIV where the hero is inevitable some patient or person who heroically tells others what to do and what needs to be done. Meanwhile, the medchemists at Merck, Abbott, roche, Amgen, Lilly, etc quietly continue to go botu their day to day work of dolving the many pressing problems we face. I still remember when Magic Johnson announced to the world he was HIV infected snd thinking as I watched him talk that I was watching a men who would be dead within a few years. Oh my gosh, why hasn't a movie been doena botuthe folks who worked tirelessly to find the dugs that have put HIv into clinial remission for msot nybodywith the disease. Een the poorest nations of the world, where the pressignneeds of jsust finding food to eat and water to drink are ebing increasingly treatimg, how goodis that?

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16. Lewis Carrol on March 20, 2014 7:41 PM writes...

`Twas brillimited for the small molecule toves
Did gyre and gimble as they fade:
All mimsy were the boiologigoves,
And the Montagu raths outgrabe.

or.....whatever NoDrugs said

Just kidding, but love the smartphone posts!

Cellbio

Permalink to Comment

17. Mr. Gladstone on March 20, 2014 9:46 PM writes...

A couple of points:

As scientists we should always be exploring/pushing the boundries of our discipline - the footprint of small molecules is giving way to other modalities

The vast majority of NCE's approved last year were small molecules, many with properties outside the prescribed molecular property constraints

Third - the arguments of large v. small molecules are still playing out. A key inflection point in this debate will be the rate of the emergence of biosimilars.

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18. Anonymous on March 21, 2014 1:09 AM writes...

The problem with biosimilars, is that society is investing (wasting) huge amounts of money just to copy the innovations that society already has. Where's the net value creation in that? At least copying generics barely costs a dime.

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19. paul on March 21, 2014 5:53 AM writes...

last year, 70% of pharma revenue was from biologics. with RNAi gaining steam and now the advent of genome engineering that works at least ex vivo for now (see Carl June's work in HIV), small molecules will be a 'smaller and smaller' slice of the therapeutics pie. i'm not sure the savior is ADCs or making small molecules a little bigger. the reality is that biologic approaches are rapidly overtaking small molecules. frankly, small molecules actually are not great therapeutic approaches given their promiscuity (in many cases), difficulty in optimization and lack of generalizability-each problem is too idiosyncratic to build much off prior developments. sadly, does not bode well for most organic chemists...

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20. Anonymous on March 21, 2014 6:52 AM writes...

@19: Exactly. Evolution has already provided all the machinery to make proteins that can perform every function in the body, so no reason to think that proteins can't be developed to perform any therapeutic function you might think of.

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21. Anonymous on March 21, 2014 8:23 AM writes...

@20 And if people really figure out how to genome edit in vivo and/or develop therapeutic mRNAs...wow. it would mean being able to target diseases at their root--revolution.

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22. barry on March 21, 2014 8:32 AM writes...

The binding energetics of small molecules aren't generally the problem. We have plenty of examples of pico-molar binders under 500 Daltons. But Lipinski carefully only addressed passive transport through membranes. Over the last three billion years, cells have evolved lots of pores and active transporters that can be exploited to get drugs past the membrane. Many natural products evade Lipinski's "Rules" by doing just this. We have yet to learn to.

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23. simpl on March 21, 2014 9:39 AM writes...

@ barry: "We have yet to learn to [get drugs to cross membranes]"

What about teniposide (natural cytotoxic linked to a sugar) or digitoxin (natural product with altered sugar residues to adjust membrane transport)?
But there is no doubt we need to learn a lot more.

Another argument which can favour chemicals is that the three million years of cell biology also applies to binding, degradation and elimination, so that biologicals often don't last long in the body.

Permalink to Comment

24. Curious Wavefunction on March 21, 2014 10:16 AM writes...

#9:

1. The price of biologics may be higher because they are more effective in certain cases. But they hit only a few targets as of now (TNF, anyone?) so whether this is a more general feature is something that remains to be seen.

2. It's not just a matter of costs, it's also a matter of patient compliance. A diabetes patient will always be happier taking a cheeper pill than inject himself everyday with an expensive antibody.

3. This sounds like a wishlist more than anything else. Sure, there have been promising delivery strategies but whether that would translate to the ability to deliver an arbitrary antibody to an arbitrary part of the body is something that's not certain at all. And delivering biologics across the BBB is very likely going to remain an unsolved problem on a general level.

Also, as someone pointed out in my post, one of the virtues of small molecules is that they can actually be selectively non-selective, which means you can likely do targeted polypharmacology better with them than with antibodies.

None of this takes anything away from the advantages of biologics for treating specific disorders but I have little patience with those who see them almost completely replacing small molecules in most therapeutic areas in a few decades.

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25. Anonymous on March 21, 2014 10:41 AM writes...

@2 barry: "The binding energetics of small molecules aren't generally the problem. We have plenty of examples of pico-molar binders under 500 Daltons."

...except that's only for binding to "small pockets" (ion channels, receptors, active sites). There is no way a small molecule could bind that tightly and specifically to the flat exposed surface of a protein molecule.

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26. Anonymous on March 21, 2014 10:47 AM writes...

@24: "I have little patience with those who see them almost completely replacing small molecules in most therapeutic areas in a few decades."

Fair enough, though I do think small molecules are leading the curve of diminishing returns, and rapidly reaching the point where they are not worth the investment, compared with buying a few lottery tickets.

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27. Puff the Mutant Dragon on March 21, 2014 1:20 PM writes...

One area where biologics will probably never replace small molecules: antibiotics. You find me an injectable biologic with horrible PK that costs a bajillion to make and I'll find you an orally bioavailable small molecule that kills bacteria much more effectively and far cheaper.

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28. Puff the Mutant Dragon on March 21, 2014 1:30 PM writes...

Speaking of PK and biologics...one of my big interests for a while has been development of LC-MS assays to quantify biologics in plasma. Obviously right now your method of choice for quantifying biologics for PK studies is ELISA. LC-MS would offer all kinds of advantages but there are some difficult challenges to overcome. Lot of interesting work going on in this area right now

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29. Anonymous on March 21, 2014 3:12 PM writes...

Nimbus finding it a bit harder to place their SBDD derived small moleules than they expected? Time to move on to new pastures

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30. barry on March 22, 2014 7:49 AM writes...

The binding energetics of small molecules aren't generally the problem. We have plenty of examples of pico-molar binders under 500 Daltons. But Lipinski carefully only addressed passive transport through membranes. Over the last three billion years, cells have evolved lots of pores and active transporters that can be exploited to get drugs past the membrane. Many natural products evade Lipinski's "Rules" by doing just this. We have yet to learn to.

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31. Anonymous on March 22, 2014 9:25 AM writes...

@30 barry: See 25.

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