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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 21, 2014

Molecular Printing of Drug Molecules. Say What?

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Posted by Derek

Update: the author of this paper has appeared in the comments here (and elsewhere) saying that he's withdrawing the paper. These are apparently reviewer's comments on it, although I have no way of verifying that. Many of them don't sound like the comments I might have expected. There's more here as well.

Here we have one of the oddest papers to appear in Drug Discovery Today, which is saying something. The journal has always ranged wider than some of the others in this space, but this is the furthest afield I've seen to date. The title is "DrugPrinter: print any drug instantly", and I don't think I can do better than letting the abstract speak for itself:

In drug discovery, de novo potent leads need to be synthesized for bioassay experiments in a very short time. Here, a protocol using DrugPrinter to print out any compound in just one step is proposed. The de novo compound could be designed by cloud computing big data. The computing systems could then search the optimal synthesis condition for each bond–bond interaction from databases. The compound would then be fabricated by many tiny reactors in one step. This type of fast, precise, without byproduct, reagent-sparing, environmentally friendly, small-volume, large-variety, nanofabrication technique will totally subvert the current view on the manufactured object and lead to a huge revolution in pharmaceutical companies in the very near future.

Now, you may well read that and ask yourself "What is this DrugPrinter, and how can I get one?" But note how it's all written in the conditional - lots of woulds and coulds, which should more properly be mights and maybes. Or maybe nots. The whole thing is a fantasy of atomic-level nanotechnology, which I, too, hope may be possible at some point. But to read about the DrugPrinter, you'd think that someone's ready to start prototyping. But no one is, believe me. This paper "tells" you all the "steps" that you would need to "print" a molecule, but it leaves out all the details and all the hard parts:

Thus, if DrugPrinter can one day become a reality it will be a huge step forward in drug discovery. The operator needs only to sit down in front of a computer and draw the structure of compound, which is then inputted into the computer, and the system will automatically search by cloud computing for suitable reaction conditions between bond and bond. . .

That actually captures the tone of this paper pretty well - it exists on a slightly different plane of reality, and what it's doing in Drug Discovery Today is a real mystery, because there's not much "Today" in it, for one thing. But there's something else about it, too - try this part out and see what you think:

Thus, this novel protocol only needs one step instead of the five-to-ten steps of the current synthesis process. In actual fact, it is even better than click chemistry, with lower costs and with better precision of synthesis. A world-leading group led by Lee Cronin has made advances with the technology named ‘Chemputer’. However, it is different to our concept. We specifically address the detail of how to pick up each atom and react. We also disagree that it is possible for anyone to simply download the software (app) from the internet and use it to print one's own drug. It is not feasible and should be illegal in the future.

Some of this, naturally, can be explained by non-native English usage, although the editorial staff at DDT really should have cleaned that up a bit. But there's an underlying strain of grandiose oddness about the whole manuscript. It makes for an interesting reading experience, for sure.

The paper proposes a molding process to fit the shape of the desired target molecule, which is not prima facie a crazy idea at all (templated synthesis). But remember, we're down on the atomic scale here. The only thing to build the mold out of is more atoms, at the same scale as the material filling the mold, and that's a lot harder than any macroscale molding process that you can make analogies to. The MIP (molecularly imprinted polymer) idea is the closest real-world attempt at this sort of thing, but it's been around for quite a while now without providing a quick route into molecular assembly. There is no quick route into molecular assembly, and you’re certainly not going to get one from stuff like this:

Benzene has six carbon atoms joined in a ring, with one hydrogen atom attached to each carbon atom. It can be divided into six reactors for three atoms: C, H and C (Fig. 3). After inputting the chemical structure of benzene, the system will search for the best synthesis condition for each bond. The best optimal condition will be elucidated by computer and controlled by a machine with optical tweezers to pick up the reactant and the atoms of carbon and hydrogen. The carbon atom will be picked up by optical tweezers in the right position in these tiny reactors (just like a color laser printer). DrugPrinter technology will work just like a color laser printer but instead of a four-color (red, yellow, blue and black) printer toner cartridge there will be various atoms.

Right. The computer will search for the best reaction conditions for building up benzene by individual carbon atoms? There are no best conditions for that. You can make benzene from acetylene, if you’re so minded, but you need metal catalysts (Reppe chemistry). And how are these “conditions” to work inside some sort of benzene-shaped mold? How are the intermediates (propene? butadiene?) to be held in there while another carbon atom comes in? Making benzene in this manner would be Nobel-level stuff, and this paper’s just getting warmed up:

. . .The chamber for the storage of elements is divided into three parts based on the character of each atom according to the periodic table of elements. Roughly, there are three categories: nonmetals, metals and transition metals. Of course, most drugs are organic compounds, thus it is reasonable to expect that carbon (C), hydrogen (H) and oxygen (O) will be the major consumables (just as the black toner cartridge always runs out before the other three colors in a printer). . .

I don’t know what the author’s background is, but honestly, you get the impression that it doesn’t include much organic chemistry. The whole paper is written about a world where you take individual atoms from these reservoirs and fly them down small channels “with lasers or plasma” to be caught by optical tweezers and put into the right position. Apparently, things are just going to snap together like so many molecular model pieces once that happens. Reaction mechanisms, thermodynamics, reactivity and selectivity make no appearance at all that I can see. What does make an appearance is stuff like this:

Big data is applied suddenly in any field. For DrugPrinter, we allow the user to upload their desired compound by a webserver. A cloud computing system and fast dealing and optimal of the chemical reaction must be searched immediately. All the bond–bond reactions will be collected in an intelligent system by cloud computing. Because we built a world-first intelligent cloud computing drug screening system called iScreen (http://iscreen.cmu.edu.tw/) and an integrated webserver (http://ismart.cmu.edu.tw/) including the world’s largest traditional Chinese medicine (TCM) database (http://tcm.cmu.edu.tw/), this has enabled our technology. . .

I’m not trying to be unkind here, but some of this reads rather like the spam comments that pile up on this blog and others. “The buzzword will be made by high-tech buzzword by use of buzzword systems”. None of this is real, and as speculation it’s not too exciting, either. Eric Drexler is far more interesting reading – you can certainly find many things to argue about with him (as Richard Smalley famously did), but he’s thought about these problems in a useful way, as have many others. Drexler’s name, by the way, appears nowhere in this current paper, although the whole thing reads like a smudged tenth-generation photocopy of his work from the 1980s.

And that brings up an editorial question: who reviewed this? How did the staff at Drug Discovery Today find this worth publishing in its current form? I have no problem with them running papers about speculative nanotech chemical synthesis, I should add. I like that stuff; I like reading about it. But I don’t like reading hand-waving hoo-hah illustrated with videos of traditional egg-cake molding machines (I kid you not). As published, I found this paper to be an irritating, head-shaking, eye-rolling waste of time, and I would gladly have said so in a referee report. I see that Chemjobber is baffled as well. Who wouldn’t be?

Comments (46) | Category: Chemical News | The Scientific Literature


COMMENTS

1. Mike Parker on April 21, 2014 7:17 AM writes...

It does read like science fiction, doesn't it? It is like the way an episode of Star Trek tries to explain some piece of their technology. It is vaguely plausible for some distant future, but it just sounds funny to someone who known science.

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2. Pete on April 21, 2014 7:23 AM writes...

Don't be so cynical. This is triumph for the democratization of science. Peer review is grossly overrated anyway although I'd love to sample whatever the reviewers were smoking when the waved this one through.

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3. newnickname on April 21, 2014 7:44 AM writes...

This whole process seems highly wasteful to me when you can just as easily put the patient in a machine, press a button (or combination of buttons for really complicated diseases) and have the machine repair or replace the damaged molecules underlying the patient's disease. I know this sounds reminiscent of Drexler's nanobots but that requires separate prior fabrication of the nanobots. The machine I describe skips the nanobots and resorts to fabrication of a different sort.

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4. Miramon on April 21, 2014 4:34 PM writes...

The reference to Big Data as a magical computing resource is particularly pathetic. Big Data is just another data processing technique, not a magic fix for "not knowing how to do stuff".

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5. Pierre on April 21, 2014 4:35 PM writes...

It sounds like an article accepted just in time for April Fools' Day, don't you think???

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6. enotty on April 21, 2014 4:37 PM writes...

...hhmmm.... a slow day for Derek?... we need to find more pithy phodder phor pondering (pronounce it phour times phast...)

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7. Seriously on April 21, 2014 4:49 PM writes...

This guy is the worst computational chemist out there. Go look at his other papers. While some might be better than this, they are all trash. He self-cites like it is going out of style. His work is never tested in an experiment. He makes grandiose claims without any proof. Sometimes the molecules he proposes are just plain wrong. Can you say not soluble?

I really hope this article is destroyed, quickly. I also hope it takes down this obviously low-quality researcher. His papers are garbage, his science is garbage, everything he touches is garbage.

Sorry if I'm being mean, but I've asked for his papers to be retracted by journals multiple times as they are such obvious trash that clearly wasn't reviewed. People don't want to get involved destroying utterly useless junk science because they'd have to stop doing their own work for a few minutes. We're all so busy, no one has time to remove garbage science articles. Great scientific system we've got going here.

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8. Wowchem on April 21, 2014 4:51 PM writes...

Sweet, I'll keep this machine next to my car the folds into a suitcase.

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9. Project Osprey on April 21, 2014 4:53 PM writes...

If a North Korean news reader were to make a chemistry paper it, would sounds exactly like this...

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10. Justin Peukon on April 21, 2014 5:48 PM writes...

I hope the machine will be provided with "R" and "S" labeled cartridges for carbon. Could be useful for printing chiral molecules.

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11. Squib on April 21, 2014 5:59 PM writes...

"DrugPrinter technology should be feasible within 20 years. I predict that our team will make the prototype of DrugPrinter available within five years. However there are still some bottlenecks that need to be overcome, although its application is needed urgently in pharmaceutical- and nano-material fabrication and this will expedite the process."

Surprised nobody picked up on this gem. Shouldn't the technology be feasible BEFORE you have a prototype available?
Also, even if this could work, you'd only be making one molecule at a time. Unless the throughput if this was very high it would take a long time to make the 0.01 mg whatever the smallest amount needed for your screening would be.

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12. Jim C on April 21, 2014 6:41 PM writes...

"Danger

Just imagine if one day you could simply download an app from the internet and then print your own drug out at home, it would be a worldwide disaster. Chronic drug abusers or gangsters would produce amphetamines or other narcotics in abundance. The drug abuse problem would soar beyond all comprehension if DrugPrinter was available to the general public–policeman and lawyers would be as busy as the chemists.

Law and morality

DrugPrinter must not become a future household product, even though there are some scientists trying to develop the apps for people to download and print their own drugs at home. It would also be dangerous if a child were to print drugs or download the wrong app from the Chemputer app store. All the printing of drugs must be approved by big pharmaceutical companies, doctors and with prescription. A law should be written that forbids people from printing drugs privately."

Ah. Rigorous analysis not only in science, but so too in the more humanities oriented thoughts. Does anyone else think that the above two paragraphs read as if they were constructed by a 9th grade student?

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13. Anonymous on April 21, 2014 7:11 PM writes...

It goes to tell you what kind of shxt DDT really is.

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14. DrSnowboard on April 21, 2014 7:16 PM writes...

He references his own paper twice refs 22 and 35 are identical , lets hear it for standards in editing eh?
Someone needs to explain the concept of molar quantities to the author, and the editors of DDT.
A new low in publishing

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15. Shocker on April 21, 2014 8:03 PM writes...

April fool....what no...This was so bad, it got progressively worse as it descended into the biggest pile of poop. I emailed the journal editor just to check and see he knew he let this through. Do not laugh it was supported by 9 grants from Taiwan, China..thankfully not the USA. How can he be affiliated with MIT. Has he gone back to school? Is he a post doc? And yet there are brilliant scientists let go everyday by pharma and this guy can get 9 grants - in shock.

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16. Seriously on April 21, 2014 8:24 PM writes...

@15, Shocker.

Interestingly, MIT makes no claim on him, except apparently giving him an email address. Can't find his name on an MIT website at all.

Yet he continues to publish some of the worst (those this is the crown jewel) computational chemistry around.

Great Job! Give him a raise! Fire some more hardworking scientists!

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17. jbosch on April 21, 2014 8:36 PM writes...

I can print drugs on any type of paper already and you can too !
You can even size them differently and get them in b&w or color.
This paper is great - I couldn't resist and distribute it to my students for their critical evaluation and see what they come up with.
This will be a great example for a class I think :-)
The problem with this paper is, I think the author actually believes what he wrote, a slightly distorted reality field around him. The replicator from Star Trek would do similar things, and they had in one of their episodes an iPad-ancestor, so why not ?
Thanks for this gem Derek

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18. Nick K on April 21, 2014 9:14 PM writes...

What was the editor thinking? DDT's credibility was never high to begin with, but after this it will be nil.

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19. Anonymous on April 21, 2014 10:23 PM writes...

Obviously, if this had only been reviewed by a chemist this steaming pile wouldn't have been published. The biologists are obviously to blame.

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20. Anonymous on April 21, 2014 10:29 PM writes...

Seriously though, how does this future fantasy get published in a "science journal"? This is worse than something one would read in Popular Science.

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21. Erebus on April 21, 2014 11:21 PM writes...

Popular Science? This wouldn't pass the review board over at Asimov's.

(...And what do the egg-cake machines have to do with anything? Haha...)

This paper is either an intentional parody, a computer-generated paper full of meaningless terminology and repetitive buzzwords, or simply the work of a lunatic. (Like that Gyre paper that was published a few years ago in "Life.")
...I kinda hope that it's just a late April Fool's joke...

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22. PC on April 22, 2014 12:06 AM writes...

i don't want drugs...print me diamond

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23. PC on April 22, 2014 12:07 AM writes...

i don't want drugs...print me diamond

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24. barry on April 22, 2014 12:16 AM writes...

It's not impossible that such a thing could be realized (we have already seen examples of bond breaking and making using an ATF) but in 2014, this is the sort of visionary/pie-in-the-sky (take your pick) fiction that conflates computer viruses with biological viruses in the current moving "Transcendence". The vision dissolves into nonsense when you try to put in details like stepping too close to a Monet Waterlillies canvas.

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25. Chemist Turned Banker on April 22, 2014 2:43 AM writes...

Completely agree that this is garbage of the first order, but don't let it upset you, guys. Do what I did. Print it out, set phasers to stun and blast it to bits

Live long and prosper (and cancel the DDT subscription)

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26. Anonymous on April 22, 2014 3:03 AM writes...

WTF. Has the author ever actually studied any chemistry or basic science? Have the editors or reviewers? This is not science, it's just some lunatic dreaming and watching too many bad sci-fi movies. I would expect more from a tabloid, or a free local newspaper.

My "fear of missing out" has been superseded by a "fear of wasting time and money on crap", so I think I will ask to cancel our DDT subscription.

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27. Anonymous on April 22, 2014 3:34 AM writes...

My favorite part is the depiction of a robot arm picking up an atom. That or the random cake factory "Supplemental."

Next up from him will probably be:
"Novel HTS using single atoms"
"QSAR using single atoms"
"Single atom cakes: they're delicious"

Also, did anyone else chortle at the "Drugputer" moniker? I swear this has to be the ramblings of an insane man or the editor seeing if anyone actually reads DDT.

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28. fluorogrol on April 22, 2014 3:50 AM writes...

"Some of this, naturally, can be explained by non-native English usage, although the editorial staff at DDT really should have cleaned that up a bit"

The article currently online is an Accepted Manuscript, i.e., it hasn't been edited yet. Some poor technical editor may well be scratching their head right now, trying to make sense of this garbage.

It's not unheard of for articles with, er, serious deficiencies spotted during technical editing to be sent back for further review/revision. In this case sending it spinning into a yawning abyss would be more suitable, though.

I notice the article has at least one zealous defender in the comments of Chemjobber's post.

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29. Torson1 on April 22, 2014 5:18 AM writes...

7. Seriously: I am happy to see that someone has at least tried to make the world aware of this guy's work. His reference list is very long indeed. Can't understand that not anyone at his previous institutions has tried to stop him.

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30. Anonymous on April 22, 2014 6:12 AM writes...

Honestly, the absolute state of this guy:

http://www.youtube.com/watch?v=CEDGCPFGuSM

Traditional Chinese medicine for gods sake.

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31. Justin on April 22, 2014 6:36 AM writes...

All the way through I'm thinking "this sounds a lot like Eric Drexler", whom I haven't thought about in about 10 years. Shame he wasn't mentioned.

I don't want to bash on the author, but the point of the article seems to be a means to pimp his other publications - in short, just an ad.

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32. Sam on April 22, 2014 6:39 AM writes...

It sounds like someone is taking "SpaceChem" literally. Other than the bit Jim C mentioned in (12), where no real thought was given to anything at all.

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