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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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March 4, 2013

Putting the (Hard) Chemistry Back in Med Chem

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Posted by Derek

While I'm on the subject of editorials, Takashi Tsukamoto of Johns Hopkins has one out in ACS Medicinal Chemistry Letters. Part of it is a follow-up to my own trumpet call in the journal last year (check the top of the charts here; the royalties are just flowing in like a river of gold, I can tell you). Tsukamoto is wondering, though, if we aren't exploring chemical space the way that we should:

One of the concerns is the likelihood of identifying drug-like ligands for a given therapeutic target, the so-called “druggability” of the target, has been defined by these compounds, representing a small section of drug-like chemical space. Are aminergic G protein coupled receptors (GPCRs) actually more druggable than other types of targets? Or are we simply overconcentrating on the area of chemical space which contains compounds likely to hit aminergic GPCRs? Is it impossible to disrupt protein–protein interactions with a small molecule? Or do we keep missing the yet unexplored chemical space for protein–protein interaction modulators because we continue making compounds similar to those already synthesized?

. . .If penicillin-binding proteins are presented as new therapeutic targets (without the knowledge of penicillin) today, we would have a slim chance of discovering β-lactams through our current medicinal chemistry practices. Penicillin-binding proteins would be unanimously considered as undruggable targets. I sometimes wonder how many other potentially significant therapeutic targets have been labeled as undruggable just because the chemical space representing their ligands has never been explored. . .

Good questions. I (and others) have had similar thoughts. And I'm always glad to see people pushing into under-represented chemical space (macrocycles being a good example).

The problem is, chemical space is large, and time (and money) are short. Given the pressures that research has been under, it's no surprise that everyone has been reaching for whatever will generate the most compounds in the shortest time - which trend, Tsukamoto notes, makes the whole med-chem enterprise that much easier to outsource to places with cheaper labor. (After all, if there's not so much skill involved in cranking out amides and palladium couplings, why not?)

My advice in the earlier editorial about giving employers something they can't buy in China and India still holds, but (as Tsukamoto says), maybe one of those things could (or should) be "complicated chemistry that makes unusual structures". Here's a similar perspective from Derek Tan at Sloan-Kettering, also referenced by Tsukamoto. It's an appealing thought, that we can save medicinal chemistry by getting back to medicinal chemistry. It may even be true. Let's hope so.

Comments (25) + TrackBacks (0) | Category: Chemical News | Drug Assays | Drug Industry History


1. Curious Wavefunction on March 4, 2013 10:56 AM writes...

"Or are we simply overconcentrating on the area of chemical space which contains compounds likely to hit aminergic GPCRs?"

This is the well-known phenomenon of library bias, explored among other researchers by Shoichet (link in my blog URL). Plus, the question of druggability must go beyond binding. There's lots of small molecules with basic amines that will bind to GPCRs but as the recent research on functional selectivity and "biased agonism" has shown, it's a very different ball game to selectively modulate desired physiological pathways through this binding.

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2. Eric on March 4, 2013 11:11 AM writes...

"The authors declare no competing financial interest."

Did you add that line, Derek, or was it automatically inserted?

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3. Teddy Z on March 4, 2013 11:28 AM writes...

Years ago HIV Integrase topped the charts for nondruggability (Figure 2.2 in my Fragment book) (I prefer the phrase non-liganability, but that is a separate discussion). Yet, lo and behold, Merck has a successful drug on the market. There are copious examples.

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4. darwinsdog on March 4, 2013 11:35 AM writes...

I think the organic synthesis breed is dying-out. It lacks survival skills in the wild of the modern work-place. Or maybe it will be maintained on non-native diets and forced breeding as a zoological curiosity (ending this analogy here).
It starts with synthesis training - it continues to get harder to fund total synthesis within the context of something of obvious value (ah, new sponge toxin with little to no real biologic interest, we hardly knew ye). Empirically I see a lot more chemistry labs funded for the kind of simple, off-shore-able industry training described in the articles. One exception being the new directions in the biology-chemistry interface but the synthesis side of it still tends to be less challenging as a rule (ahh water and protein compatible conjugation chemistries, nice to know ya). I guess its a natural evolution - the old breed was pedigreed from a total synthesis lineage and could do all kinds of carbob-carbon bond forming tricks and the new breed has limited organic synthesis training but knows how to engineer, express, purify proteins and dial internationally for the rest.

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5. lynn on March 4, 2013 12:06 PM writes...

Hey - why not look at natural products? ;-)

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6. Jeff Horsman on March 4, 2013 12:25 PM writes...

Lynn, I agree Natural Products should be reviewed, I worked in the Natural Product Group at Pfizer for many years and we were looking at very novel nat. prods as well looking to produce new variants of known products, some very interesting science which I believe could produce new drugs for the future.

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7. The Aqueous Layer on March 4, 2013 12:28 PM writes...

I think there has been some success in terms of molecules that have fairly high amounts of complexity. It started with many of the HIV protease inhibitors back in the 90s.

Even though a person or two on last week's post snickered at AbbVie's Bcl inhibitor, it's not exactly the kind of molecule that you'd ship to WuXi or ChemPartner to make a quick library of compounds. Many of the current HCV compounds in clinical trials are also quite complex, as is Brillinta.

It can be done, but you have to higher management willing to give the time required to make these types of compounds, and support the medicinal chemists that are doing this type of work, especially if they fail.

Problem is, PowerPoint slides detailing huge numbers of compounds looks great during a year-end review, and when it comes time to evaluate your scientists/programs, numbers of compounds and reactions run is SO much easier to quantify that complexity of the molecules...

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8. azetidine on March 4, 2013 12:56 PM writes...

..."Is it impossible to disrupt protein–protein interactions with a small molecule?"

I hear this over and over. The binding of Fibrinogen, a 340 kDa protein, to its receptor (gpIIb/IIIa, another large protein), can be disrupted with a tetrapeptide as well as other small molecules. Am I missing something?

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9. Chris Swain on March 4, 2013 3:04 PM writes...

I'm at the Fragments meeting in Oxford today and the guy from Astex described two projects in which they used a fragment based to approach to address protein protein interactions. Arguably more challenging but by no means impossible.

"The problem is, chemical space is large"

Something of an understatement I think, chemical is very, very, very large.

Deciding what to make may be more of an issue, at times it seems that proposing a synthetic target that can't be easily "combinatorialised" gets a strike against it.

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10. milkshake on March 4, 2013 4:13 PM writes...

I think the penicillin example that he chose is unfortunate.

1) many successful drugs, especially antibiotics and anti-cancer drugs were discovered by using cytotoxicity and growth assays or phenotypical assays in general. Detailed mechanistic understanding is not always the best starting point - a realistic disease model is. In fact, it was the over-reliance on target-based high throughput screening and rational drug design that combined with combichem revolution and genomic revolution and other lemming revolutions and together with new management methods and bureaucracy and merger megalomania. It very nearly destroyed pharma research and we all suffer the consequence (including Takashi whom I know personally).

2) As it turns out, one does not need the entire penicillin or cephalosporin core for antibacterial potency - any simple beta lactam that has a free carboxyl or sulfonyl group nearby the beta lactam will show a decent anti-microbial potency, as the example of monobactams shows. Incidentally, many simple beta lactams are quite easy to make by ketene plus imine 2+2 condensation or by cyclization of benzylesters of beta aminoacids. A beta lactam building block piece with a carboxyethyl group that I made from aspartic acid, for an unrelated project, got tested in antibacterial assay and sure enough it was pretty potent in petri dish. So I think it is actually likely that an HTS beta lactam hit could be picked without any prior knowledge of penicillin, from a library made by a parallel synthesis and it could be elaborated into a decent drug by using conventional medchem. The irreversible nature of these beta lactam inhibitors would probably be some source of initial suspicion but we have seen that other irreversible inhibitors made it to the market - Ezetimibe and Orlistat come to mind

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11. R. Coleman on March 4, 2013 5:58 PM writes...

My colleagues and I made the argument that there is something actually intrinsically undruggable about some protein binding sites, or at least harder to find a drug for, in this paper:

I, for one, still think the conclusions and data hold. Binding sites that don't present a good binding site for a small molecule to bind to (in our paper we derive such a term from biophysical properties), will be unlikely to be 'druggable', or to find a orally bioavailable drug.

I'd be pleased to be proven wrong, also I've been going after some difficult sites myself now and I think that is important to continue doing so, but with eyes open about the project and your chances.

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12. anon2 on March 4, 2013 7:16 PM writes...

Trying to define "compound apace" that seems to be favorable for drug candidates is done for very simple reasons: tiem and money.

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13. ScientistSailor on March 4, 2013 10:16 PM writes...

@4 Bad Dog, no biscuit. Do not speak ill of my sponge toxin! I spent 5 years with that molecule...

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14. Anonymous on March 4, 2013 10:36 PM writes...

Medchemist are turning into a bunch of pussies. They work on complex syntheses during their grad school work and postdocs and then go to industry and make flat molecules using Pd and amide couplings for the rest of their lives. Its probably time to pull your sleeves up and get your labcoats dirty in the lab instead of asking your associate to make cupcake molecules for you in the lab.

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15. John Wayne on March 5, 2013 9:07 AM writes...

@13: We'd love to. Unfortunately, it gets harder and harder to make interesting (read: more risky) changes to your molecules as the business aspects of drug discovery take over research space. If we don't outproduce our colleagues in Asian CRO's based on measured metrics, we are done. The currently observed metrics do not reward more challenging, higher risk/reward chemistry. So, at the end of the day, most of us use mostly bread and butter chemistry to keep our jobs and provide for our families. I believe this trend reduces the probability of success for our projects, but nobody asked me.

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16. anonymous on March 5, 2013 9:14 AM writes...

@13 I agree. Maybe if there was more chemical risk taking and less ROI talk, we would see more Diels-Alder reactions (they are *hard* you know).

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17. jon on March 5, 2013 9:33 AM writes...

You are kidding yourself if you think complex chemistry can't be done in India or China - unless you are prepared to argue the laws of physics are less favorable/different the further east one sets up a reaction (can someone send me a map that contains this line?). Complex medchem is not done because it is too expensive - that sort of work is reserved for grad schools where legions of low-paid workers empirically try every possible permutation of running a series of reactions until a natural product pops out the other end. Then a paper is written about how they knew all along that the key to Step 27 was to use a Europium reagent at -23 degrees for 11 minutes and then heat it to 68 degrees for 56 minutes. I think they call that "Rational Design".

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18. Jock on March 5, 2013 10:11 AM writes...

I agree that molecular complexity can be very useful in drugs but focusing on it alone is not the answer - it's what you do with the molecules and how you integrate them in a well thought out project that makes the difference.
Don't forget, all those post-docs you worked with who were just as good as synthesis as you are now back in India/China working for the CROs so don't bet Western med chem groups can suddenly make things they can't :-)

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19. Anonymous on March 5, 2013 10:43 AM writes...

Well, maybe its time to change things up a little bit then. You cant go on forever doing the same things and expecting a different result. If management cant support interesting and different research because it is difficult, then it is just a matter of time before we are left with two big pharmas.

I just think it is a shameful waste to have such bright people and waste their talents making "easy" molecules to fit timelines. That type of work can easily be off-shored. If this is indeed true, then off-shoring medchem makes perfect sense. You dont need graduates from Harvard, MIT and Berkeley to do Suzuki and amide couplings.

It is indeed a sorry state of affairs and perhaps a lack of leadership, vision and guts on part of senior management and on part of the medicinal chemist community. If you can't change and adapt, then it is time to become extinct.

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20. Legolas on March 5, 2013 11:08 AM writes...

Hi All,
I have read this blog for some time now. I think it is great not only for Derek's posts, but also for the really hands-on comments. I'm trying to put together some numbers and clarify some concepts. Maybe some of you can help me.
- What data do you mean/need to "validate a new target"?
- Are ex-pharma MedChems willing to move to an Academic-base center for Drug Discovery?
- Average salary of an experienced (industry) medchem and synthetic chemist?
- How does it look a typical pharma team in drug discovery stage? The idea is to enable commercial valuable IP and provide an early-stage (with a validated target) program for small biotechs and attract ES-VC money (very difficult).

I know those are maybe silly questions, but I'm really trying to push for the creation of a DD initiative with pharma people in order to leverage the federal funding expenditure for basic research in my university.

Thanks in advance

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21. TX Raven on March 5, 2013 12:22 PM writes...

@18: on the spot!
The question is not about how a compound is made or how complex its structure is.

Medicinal chemistry is about asking the right questions for the project, and making the right compound to help answer them.

So, what was the last question you asked? If someone is asking the same question and answering it for less money than you do, you can't win this game.

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22. Hap on March 5, 2013 1:47 PM writes...

You can't win the game if your team is busy forfeiting, though. None of the people to whom drug research is being sent have either found drugs (so that you have no reasonable assurance that they can do it at all, let alone better, only that they can do it more cheaply). If people really thought discovery was random (that the expensively-gained knowledge of med chemists doesn't matter), they could probably hire and train high school grads or laid-off manufacturing people to do it much more cheaply and without either IP or distance issues.

These arguments imply that effectiveness at discovering drugs is not a matter of concern now, only spending less money doing so (or rather appearing to do so). If investors aren't interested in either risk or the long term, and need to cash out soon, companies that wish to make things well and better won't exist, and jobs making things well and better won't, either. That doesn't mean that making things well or better is not worthy (because your soul is worth something, and destroying it for the benefit of short-sighted people is not even a Pyrrhic victory), just that it probably won't save anyone's job.

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23. Chemist soon to be non-chemist on March 5, 2013 4:26 PM writes...

It is because of the attitudes of the so-called "elite medicinal chemists" that I am quitting medicinal chemistry. After graduating or being a post-doc in a "top 10" organic synthesis lab, they pick up medicinal chemistry jargon and start to believe in it. "fragment-based,""high throughput synthesis," "druggability" and what not. Seriously, they talk about Lipinski's rule of 5 like it's some constitutional amendment. Sure, I can keep on fighting this losing battle if I have 1000 years of life. But why waste my life to fix a problem that can easily be "not my problem?" A medicinal chemistry Ph.D. background is a no-no in the industry.. gotta have a hard-core organic synthesis background. "You are not a real chemist" they say. Well, great! in this job market I am actually glad that I am "not a real chemist" because unlike "real chemists" I don't have to spend my time worrying about when will I get laid off. /rant

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24. TX Raven on March 6, 2013 4:30 AM writes...

Your comment made my day!

I am one guy working to make things well or better. And I don't want to destroy my spirit.

I am convinced more people with these attributes can work together and create a great drug discovery organization.

How could one start? Anyone?

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25. Anonymous on March 6, 2013 10:52 AM writes...

@23. Amen brother (or sister). I have long held that the inbreeding seen in pharma (Corey alum only interviewing Corey alum etc...)was not good for it's future.

I am seeing a lot of chemists from high profile labs applying for positions at the consumer products company I work for. Most have pharma as their msot recent position.

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