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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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April 16, 2013

What's Translational Synthesis, Anyway?

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Posted by Derek

There's another paper in the Nature Chemical Biology special issue that I wanted to mention, this one on "Translational Synthetic Chemistry". I can't say that I like the title, which seems to me to have a problem with reification (the process of trying to make something a thing which isn't necessarily a thing at all). I'm not so sure that there is a separate thing called "Translational Synthetic Chemistry", and I'm a bit worried that it might become a catch phrase all its own, which I think might lead to grief.

But that said, I still enjoyed the article. The authors are from H3 Biomedicine in Cambridge, which as I understand it is an offshoot of the Broad Institute and has several Schreiber-trained chemists on board. That means Diversity-Oriented Synthesis, of course, which is an area that I've expressed reservations about before. But the paper also discusses the use of natural product scaffolds as starting materials for new chemical libraries (a topic that's come up here and here), and the synthesis of diverse fragment collections beyond what we usually see. "Fragments versus DOS" has been set up before as a sort of cage match, but I don't think that has to be the case. And "Natural products versus DOS" has also been taken as a showdown, but I'm not so sure about that, either. These aren't either/or cases, and I don't think that the issues are illuminated by pretending that they are.

The authors end up calling for more new compound libraries, made by more new synthetic techniques, and assayed by newer and better high-throughput screens. Coming out against such recommendations makes a person feel as if they're standing up to make objections against motherhood and apple pies. And it's not that I think that these are bad ideas, but I just wonder if they're sufficient. Chemical space, as we were discussing the other day, is vast - crazily, incomprehensibly vast. Trying to blast off into it at random (which is what the pure DOS approaches have always seemed like to me) looks like something that a person could do for a century or two without seeing much return.

So if there are ways to increase the odds, I'm all for them. Natural-product-like molecules look like as good a way as any to do this, since they at least have the track record of evolution on their side. Things that are in roughly these kinds of chemical space, but which living organisms haven't gotten around to making, are still part of a wildly huge chemical space, but one that might have somewhat higher hit rates in screening. So Paul Hergenrother at Illinois might have the right idea when he uses natural products themselves as starting materials and makes new compound libraries from them.

So, who else is doing something like that? And what other methods do we have to make "natural-product-like" structures? Suggestions are welcome, and I'll assemble them and any ideas I have into another post.

Comments (53) + TrackBacks (0) | Category: Chemical News | Drug Assays


COMMENTS

1. A. Postdoc on April 17, 2013 12:40 AM writes...

For all his talk, has Schreiber contributed to any drugs?

We've been doing a faculty search at my present institution, and someone clearly decided we should hire a Schreiber trainee, because that is all we've interviewed. None of them have any plans for how to do research without his robots and screening techniques, and none of them have a plan for how to get money to buy their own robots.

What a joke they've made of science

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2. gippgig on April 17, 2013 3:12 AM writes...

Translational synthesis is how proteins are made.
(On a serious note, have any synthetic biologists proposed developing some sort of genetically encoded polyketide synthesis?)

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3. nr on April 17, 2013 3:50 AM writes...

Does ELT offer a possible way forward here. Chemical space is vast and ELT would enable cost effective screening. The IF is whether the chemistries could be enabled to allow ELT (beyond triazines and amides !)

Is the screening world going to polarise into small screens (fragments or directed sets based on structural knowlege) and megascreens - with conventional HTS (like the European Lead Factory and many of the academic attempts to replicate Big Pharma collections) becoming redundant

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4. JS on April 17, 2013 4:27 AM writes...

Warp Drive Bio, launched by Third Rock Ventures and Sanofi, has an interesting model for natural product discovery.

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5. patentgeek on April 17, 2013 7:43 AM writes...

@ Derek: H3B is a wholly owned unit of Eisai, Inc. Schreiber (and Golub) are on the Board, and Lisa Marcaurelle (co-author of the paper) came from Broad.

@gippgig: Kosan Biosciences was a company whose platform was based on making novel analogs of polyketides by genetic engineering of biosynthetic pathways. I think they were bought by BMS around 2008.

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6. Anonymous on April 17, 2013 8:00 AM writes...

Sounds like same pig new lipstick color

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7. Anonymous on April 17, 2013 8:01 AM writes...

I've always wondered if this infatuation with natural products is a little misguided. We see these big, elaborate, beautiful, difficult to synthesize structures and think to ourselves: "Wow, how did nature come up with that? All this complexity must be needed for function." And so we begin to think that maybe we need to make structures like that to get the functions we are looking for (i.e. drugs).

But we forget that nature actually has a much more limited toolbox of synthetic chemistry than we do. Peptide, alkaloid, polyketide, and terpene biosynthesis account for the vast majority of natural product structures. Nature doesn't do Suzuki or Buchwald or even cycloadditions. So of course, when confronted with a binding problem, it is forced to resort to an overly complex structure because the toolkit doesn't allow for an atom-economical solution.

That's not to say NPs are not useful, because any active compound, regardless of its complexity, is valuable. It teaches us about the binding site and the pharmacophore. It can help validate a target. IT could even be a drug candidate itself. I'm just not sure that making boatloads of these complex structures is the best way to find new drugs.

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8. M on April 17, 2013 8:30 AM writes...

Interestingly, I recently heard Schreiber speak and he had a new twist on DOS which raised my eyebrows. In the Q&A session he said something to the effect of that the D in DOS should mean biological diversity, as in the types of biological targets hit, rather than chemical structural diversity.

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9. Hap on April 17, 2013 8:35 AM writes...

1) Except that one might figure that the proteins and other systems of living things are adapted to what they can make - if our cells could do Suzuki couplings, receptors might look a lot different as well. All those proteins might be in part optimized on what the cells and other things can make. If that were the case, then looking at NPs would make a lot of sense; even if you don't really want all that complexity in your final drug, the NP ligand tells you what you might need to make a simpler ligand for use as a drug.

Looking at NPs is like the famous line about robbing banks - you target them because they are where the known binding structures are.

2) How do you target biological diversity? At least we have a (faint) idea of what chemical diversity is and how to work at it. How do you make biologically diverse libraries?

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10. Hap on April 17, 2013 8:40 AM writes...

1) Except that one might figure that the proteins and other systems of living things are adapted to what they can make - if our cells could do Suzuki couplings, receptors might look a lot different as well. All those proteins might be in part optimized on what the cells and other things can make. If that were the case, then looking at NPs would make a lot of sense; even if you don't really want all that complexity in your final drug, the NP ligand tells you what you might need to make a simpler ligand for use as a drug.

Looking at NPs is like the famous line about robbing banks - you target them because they are where the known binding structures are.

2) How do you target biological diversity? At least we have a (faint) idea of what chemical diversity is and how to work at it. How do you make biologically diverse libraries?

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11. A.nother Postdoc on April 17, 2013 8:40 AM writes...

#1 - What an incredibly ignorant statement! You clearly have no idea what Schreiber has done for the field of medicine, nor his myriad of trainees.

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12. Utbiotech on April 17, 2013 8:47 AM writes...

Good point, it's interesting for me to find new compound libraries which may have better application for drug development.

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13. will on April 17, 2013 8:48 AM writes...

I don't know what his EXACT contribution was, but ~15 years ago Schreiber certainly did a bunch of work on rapamycin, which is an enormously useful drug both in drug eluting stents and organ transplants. at least one derivative of rapamycin is also approved (everolimus)

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14. Hap on April 17, 2013 8:58 AM writes...

Someone listed some of his postdocs:

http://pipeline.corante.com/archives/2010/09/28/nobel_season_2010.php#453343 (also next comment)

From the comments: Albers, Tan, Kiessling, Jamison (grad student), Hoveyda, Porco, John Chen, Sammakia, Taunton, Stockwell (grad student?), Weiss, Peterson, Wandless. Not all that bad a list.

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15. darwinsdog on April 17, 2013 9:11 AM writes...

OK, dinosaurs begat petro which begat almost everything in the (Aldrich) catalog which begat all the screening libraries which begat pharma industry hits/leads/drugs. Now tell me again about natural-product-LIKE cmpds and why this synthetic organic molecule over here is more like a natural product than that synthetic organic molecule over thar. Speak very slowly so I can understand.

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16. patentgeek on April 17, 2013 9:16 AM writes...

@13: Schreiber played a big role in the early '90s in elucidating the mechanism of action of FK506 (FK506-FKBP12-calcineurin complex) and rapamycin (rapa-FKBP12-TOR complex). The book "Billion Dollar Molecule" is a good read on the interplay between Schreiber and Vertex in this regard.

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17. Anon on April 17, 2013 9:37 AM writes...

#1: Schreiber has not expressly discovered blockbuster drugs but he has contributed enormously to the general philosophy of chemical biology and drug discovery. His real influence - evident in his training of many - has been to offer a way of thinking about drugs, their synthesis and their mode of action that was missing before. Schreiber is one of those people who should be honored for their lifetime achievements and philosophical influence on the field rather than for a specific discovery.

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18. JB on April 17, 2013 9:58 AM writes...

A bunch of us at the Broad are following this thread, happy to have a discussion-
@5- Sarathy also used to work at the Broad.
@14- Aside from the "I know it when I see it" method, there have been several attempts to quantify the structural differences of classes of molecults in terms of fraction of sp3 carbon, chiral centers, etc. I think Derek's referenced the flatland one before- J. Med. Chem 2009, 6752-6.

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19. really? on April 17, 2013 10:35 AM writes...

#16 - how about James Black, George Hitchings, Trudy Elion - just to name a few that actually changed how to think about drugs, discovered drugs and didn't master in 'spin'? Schreiber should be respected as a talented synthetic chemist who has also pioneered many areas of chemical biology. Drug discovery - not so much (which is OK).

As far as DOS goes, NP's are special b/c evolution has driven their optimization. I remain highly skeptical that making compounds that look like NP's, but aren't, is worthwhile. They seem to be mostly an excuse to do fanciful chemistry (which I am all for as long as the rationale is not bogus). Also, the notion that the typical heterocyclic drugs (gleevec etc...) are 'flat' and that you need chirality to interact w a protein active site in a chiral binding mode is nonsense. Show me one 3D structure of a compound with rotatable bonds that is in an achiral conformation when bound to its protein target. NP's are 'complex' to us b/c nature's synthetic tool kit is not the same as the organic chemist's. 'Simple' small molecules w/o 3D 'complexity' can and do adopt high potency and chiral conformations in the active sites of proteins that they target - and they can be highly selective. I will be convinced by data, but the arguments made for DOS in the literature do not bear examination.

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20. B on April 17, 2013 11:17 AM writes...

@2: Synthetic polyketide synthase pathways are a huge area of research. Many people are working on them. They are notoriously difficult though, as the interactions between each module and it's respective interacting partners is not well understood. The other issue is very low yields. However, custom synthesis via synthetic polyketide pathways is on the horizon I think.

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21. darwinsdog on April 17, 2013 11:27 AM writes...

@17 - thanks but really more of a rhetorical question in full awareness of the c-hybridization and chirality notions about NPs. Chemists accept error in measurement but not concepts - anytime one has to add the suffix "-like" (or "-ish" "-esque" etc) to describe something then one has already failed to be clear in what is meant: Law-like, life-like, job-like, drug-like, equality-like. Euclid had no need for triangle-like to describe a square.

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22. JAB on April 17, 2013 11:29 AM writes...

B. R. Balthaser, M. C. Maloney, A. B. Beeler, J. A. Porco, Jr., and J. K. Snyder. Remodelling of the natural product fumagillol employing a reaction discovery approach. Nat.Chem. 3:969-973, 2011.

A nice example of what can be done starting from an abundant natural product.

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23. MoMo on April 17, 2013 12:15 PM writes...

Ye Gods! SS and his posse have coined another catch phrase for investors!
While I like the fact H3 Biomedicine is one of the new-age touchy-feely companies that spring from the Cambridge quagmire, let's give them a chance to be successful before the fangs come out!

One measure of a chemists' success is whether the anti cancer drugs they discover are actually USEFUL and AFFORDABLE and COVERED BY INSURANCE.

I do not see this in SS's past accomplishments but I sure like those crazy molecules he and his myriads make!

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24. anon on April 17, 2013 12:17 PM writes...

Translational science is studying how to make practical impact, by definition on a macro scale, of discoveries that were made in the lab on a micro scale.

Thus taking these somewhat theoretical breakthroughs and making them have an real-world impact. As an example, use a gene knockout study paired with a tool compound study as your base, take it studying better compounds in animal disease models and then usher it solidly on the path toward treating humans in the clinic and in the marketplace. That's translational.

Thus to me "translational synthesis" would mean something like developing an safe and efficient kilogram production process from what began as a milligram synthesis in the lab. Or in other works, process chemistry. Which doesn't need a new name.

Unfortunately, people who live on self-promotion have to come up with new catch phrases every now and then to stay in the limelight, whether the catch phrase makes any sense or not. Or in this case, you use it when the important and very smart balding man dressed all in black really likes the way it sounds!

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25. Anonymous on April 17, 2013 12:18 PM writes...

While I agree that Nat. Prdts are a useful group to screen to find both tools and drugs, I don't think that makes them any better than synthetic small molecules that are not designed based on NPs. So I would screen natural products based on the idea that evolution may have shaped them, but not random organic molecules that look complex, but DON'T have natural selection designing them.

For many complex natural products, there are much simpler compounds that are easier to make, lower MW, higher potentcy, safer, etc. For example morphine and fentanyl, amphotericin B verses small molecule anti-fungals (imidazoles, triazoles, etc) and a few others, so being a large, complex molecule is not always needed.

However, there are still some natural products with great uses, ivermectin, many classes of antiobiotics, and many more examples; I would not synthesize a random molecule with 7 rings just because ivermectin contains that many.

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26. anon the II on April 17, 2013 12:29 PM writes...

This article, like the original DOS article, would make good reading if it didn't have such a pedantic tone to it.

"I'm smart, you're an idiot. Here's why."

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27. Anonymous on April 17, 2013 1:38 PM writes...

Let's not forget the most important natural product of them all: Resveratrol. And it has a MW of only 228 and no chiral centers. How does it get any better than that?

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28. Bobby Shaftoe on April 17, 2013 1:43 PM writes...

Re: 18's comment that "As far as DOS goes, NP's are special b/c evolution has driven their optimization." While it may be true that NP's are optimized by evolution, the question remains poorly answered as to what they were optimized for. For instance I'm assuming there is very little selection pressure on sea squirts in the Indian Ocean to produce compounds for the treatment of human pathology.

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29. Hap on April 17, 2013 2:09 PM writes...

26: Being vaguely selective would be a help.

27: No, but they do have to deliver their compounds to other organisms, and they have to arrive at their targets. In some cases, that could be two steps ahead of where random compounds are. In some cases (antibiotics, antitumors, antifungals), NPs are optimized for nearly the mission that we want of them or their analogs. In most other cases, pressures lead to NPs that bind selectively to a limited number of receptors with significant affinity, again often at least one step ahead of randoms. That may make them useful as tools or as leads for discovering better ones (or even new targets).

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30. patentgeek on April 17, 2013 2:15 PM writes...

@27: " For instance I'm assuming there is very little selection pressure on sea squirts in the Indian Ocean to produce compounds for the treatment of human pathology."

Not as such, but the considerable commonality of many biological pathway components between organisms far removed on the phylogenetic tree suggests that many NPs are likely to possess useful biological activity in primates (us). Marine sponges have been extremely fruitful sources of bioactive compounds. Wasp and snake venoms are useful sources of new glutamate antagonists, because in their targeted species Glu drives muscle action; in humans Glu is a CNS transmitter and pro-convulsant; thus the venoms provide departure points for anti-convulsants; and so on.

Are you a Neal Stephenson fan (Cryptonomicon)?

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31. Bobby Shaftoe on April 17, 2013 2:47 PM writes...

Hap, I agree that there are cases where NPs may have been optimized for some of the properties we find desirable in drug discovery and that NPs have clearly been useful as a source for starting points for drugs (or as drugs themselves). However, it is simply not valid to extrapolate and generalize that therefor NPs have some deified status over NP-like or DOS compounds without sufficient data supporting such a claim. I can point out plenty of natural products that are poorly cell penetrant (maybe they were optimized for that!), that have multiple targets, and/or that have no (heretofore) known biological activity of interest. There are also many cases where ortholog proteins or signaling pathways are radically divergent in pairs of species closer than sea squirts and humans.

patentgeek, yes, I am an NS fan. Anathem is quite good, and the concept of Diax's rake ("Never believe a thing simply because you want it to be true") applies here.

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32. Hap on April 17, 2013 3:31 PM writes...

I don't know that we know that NPs work better than a random subset of compounds because we really haven't sampled many of the possibles (that 1e60 thing again). It's also valid that evolution doesn't have any purpose in mind, much less our purposes, so we can't assume that compounds selected will be better than others - they were the best of what the organism could get to, given lots of time and previous steps. We do know that NPs work for some things, and that some of the things on which they do work are interesting.

NPs are usually selected by people for work because they do something. The compounds derived from them may be better or worse than those in directed DOS or combi libraries - it probably depends on the lead compounds, and by how far you can stray from a lead before a compound stops acting like the lead and starts acting like something else. I don't have any idea how that correlates to the origin of the lead.

There has been some comparison between DOS, natural product, and combi libraries, although not for activity but for size, shape, and lipophilicity). In some cases, the properties they may have may not be relevant - antibiotics were excluded from Lipinski's set, for example.

I think NPs might be quicker ways to get at some properties because at least they constitute moves in the same game as the one we're trying to play, even if they're not on the same board. There are certainly better moves, but I don't know if we know enough of the board to guess them.

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33. Chemjobber on April 17, 2013 7:33 PM writes...

I just want to say that "Bobby Shaftoe" is a awesome screen name.

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34. KinaGuy on April 17, 2013 7:44 PM writes...

A huge advantage of natural products is that they are all designed to cross membranes. Has there been an anlysis of DOS or DCS (diverted chemical synthesis) approaches with regard to permeability?

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35. Bobby Shaftoe on April 17, 2013 8:26 PM writes...

@KinaGuy, I don't know which word you used is worse between "all" or "designed"....

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36. Bobby Shaftoe on April 17, 2013 8:27 PM writes...

@KinaGuy, I don't know which word you used is worse between "all" or "designed"....

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37. Imaging guy on April 17, 2013 9:27 PM writes...

Currently about 9000 endogenous small molecule metabolites which can be called “natural products” have been identified in human. The list (human metabolome database or HMDB) goes up to more than 40,000 if exogenous drugs, foods, toxins and pollutants human ingests or comes into contact are included. Some are trying to identify human proteins which interact with human endogenous metabolites (e.g. “Extensive in vivo metabolite-protein interactions revealed by large-scale systematic analyses”). While we are looking for new natural products in soil bacteria, marine and land creatures to treat human diseases, I wonder how many human natural products are currently used 1) to treat diseases of animals and 2) for other purposes (urea?).

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38. Jack Shaftoe on April 17, 2013 9:58 PM writes...

@31,

Seeing as we are hi-Jacking (ha-ha) the thread: Cryptonomicon is "quite good"; Anathem is a masterpiece, man.

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39. gippgig on April 17, 2013 11:01 PM writes...

I didn't mean combining PKS genes to make new products; I meant an entirely new system in which a nucleotide (or something else) sequence is directly translated into a polyketide similarly to how a nucleotide sequence is translated into a protein.

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40. milkshaken on April 18, 2013 4:14 AM writes...

translational synthesis is a specific subfield of synthetic organic chemistry employed by chemical biology groups in innovative way that makes possible for new buzzwords to be directly translated into new sources of research funding

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41. Anonymous on April 18, 2013 4:40 AM writes...

Hey A.Postdoc, does your University really not have any robots?

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42. petros on April 18, 2013 7:00 AM writes...

@gippgig:

Kosan were indeed bought by BMS

UK-based Biotica, based on work from Jim Staunton's group at Cambridge, also used to work on this. The administrators were appointed in January 2013

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43. noname on April 18, 2013 7:32 AM writes...

@37 Imaging Guy:

I think what you're talking about is the "metabolome." There was a paper a few years back describing microarrays of metabolites, which were used to profile the reactome of various cell types. I think it was in Science or Nature.

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44. DannoH on April 18, 2013 8:45 AM writes...

#38: I was just about to make the Cryptonomicon reference! Beat me to it, however have not read Anathem, thanks for the recommendation.

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45. SVR on April 18, 2013 9:06 AM writes...

I truly wonder how the corresponding author in this paper treat her coworkers?

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46. Anonymous on April 18, 2013 9:14 AM writes...

@45:

Where the heck did that come from? We can disagree about the science, but why get personal? I've met the author at conferences and she is a pleasant, funny, down to earth scientist. Why go there?

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47. barry on April 18, 2013 9:19 AM writes...

re #34
That's nonsense. But of course as soon as chemists start modifying NPs we change (at minimum) their logP and their MW, so the transport properties of the cmpds in the derived libraries may be quite different from those of the parent NP

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48. LM on April 18, 2013 9:57 AM writes...

@46

Thank you...

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49. Bobby Shaftoe on April 18, 2013 10:02 AM writes...

@SVR #45: That is one inappropriate post. It is one thing to debate scientific issues and be snarky. It is quite another go after someone personally, even by implication. I've met the corresponding author on several occasions and was favorably impressed with her as an individual and as a scientist.

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50. Hiro Protagonist on April 18, 2013 10:49 AM writes...

Snowcrash

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51. Ethan Perlstein (@eperlste) on April 18, 2013 11:10 AM writes...

As someone who was an actual trainee in the Schreiber lab (grad student, 02-06), I find this comment thread both amusing and disturbing. Haters are always going to hate, and trainees will always (okay, usually) defend their advisors, but anyone who claims Stuart Schreiber hasn't contributed to drug discovery writ large needs to have their head examined. Just start with rapamycin and HDACs. As was pointed out already, rapamycin is an actual drug and some day selective-HDAC modulators will be drugs, too.

But that clearly has nothing to do with DOS or natural products per se. Part of the rush of being in the Schreiber lab was that the assembled team of chemists, biologists and informaticists made it possible do cool albeit still very academic HTS and at the same time explore mechanism of action. If I had to make common cause with anyone in this thread it would be patentgeek. For years in the Schreiber lab we would debate flat vs globular, etc., and the chemists would have their notions and the biologists (like me) would have theirs.

I was of the mind that if a chemist is going to make a library, why throw a tiny dart into the vastness of chemical space when you can leverage evolution and start with a validated scaffold? Obviously it would be nice if one knew something about the underlying pathophysiology of a disease and identified a NP that targets germane pathways, rather than picking a NP because it looks cool or its synthesis was an exciting cerebral challenge.

Also, no one here is talking about leveraging NPs in other ways that don't have anything to do with structure or chemical properties. In my thesis work, I used the NP rapamycin in modifier screens of "boring" commercial libraries. The resulting modifiers of rapamycin are chemically unsexy, but some of them have very interesting biological effects.

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52. patentgeek on April 18, 2013 3:43 PM writes...

This thread is aged, but a couple more comments:

@50: I'll see your Snow Crash and raise you Reamde and the Baroque Cycle to boot!

@51: Thanks for your thoughtful post. I enjoyed your "the rush of being in the Schreiber lab." I've known Stuart for > 35 years, since we were undergrads together at U.Va., and always relished his enthusiastic attitude that chemistry was just the coolest thing imaginable. Whether or not everybody agrees with his views on all things, his drive to make the chemist's perspective central to biology is laudable.

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53. paperclip on April 18, 2013 4:08 PM writes...

@39: That would certainly be a challenge, including getting the polyketide to condense and fold in the way you want to, as well as carrying out reductions and methylations when needed. Such a system might be better suited for some of the nonribosomal peptides.

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