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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 18, 2012

How Do These Things Get Published?

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Posted by Derek

Update: I've heard from both the lead author of this paper and one of its reviewers, and I've written a follow-up post on this subject, as well as revising this one where shown below.

I've been saved the trouble of demolishing this J. Med. Chem. paper - the Practical Fragments blog has done it for me. I really hate to say such things, but this appears to be one of the worst papers that journal has published in quite a while.

The authors start out with a small, poorly documented (update: the compounds are, in fact, in the paper's supplementary information, but see the follow-up post) library of fragment compounds. They screen these against dihydrofolate reductase, and get a few possible hits - mind you, there's not much correlation between the numbers and any potency against the enzyme, but these aren't potent compounds, and fragment-level hits don't always perform in high-concentration enzyme assays. But what happens next? The authors string these things together into huge dimeric molecules, apparently because they think that this is a good idea, but they get no data to support this hypothesis at all.

Well, their potency goes from low millimolar to low micromolar, but as Teddy Z at Practical Fragments points out, this actually means taking a terrible beating in ligand efficiency. All that extra molecular weight should buy you a lot more potency than this. There's some hand-waving docking of these structures - which the authors themselves refer to as "poorly optimized" - and some inconclusive attempts at X-ray crystallography, leading to uninterpretable data.

And that's it. That's the paper. This on a class of enzymes that's been worked on for decades, yet. (Update: this characterization is completely wrong on my part - see the follow-up post linked to above for more). Again, I hate to be unkind about this, but I cannot imagine what this is doing in J. Med. Chem., or how it made it through the editorial process. When you submit a scientific manuscript for publication, you open yourself to comments from all comers, and those are mine.

Comments (29) + TrackBacks (0) | Category: Infectious Diseases | The Scientific Literature


COMMENTS

1. RB Woodweird on April 18, 2012 9:55 AM writes...

"When you submit a scientific manuscript for publication, you open yourself to comments from all comers, and those are mine."

Ah, but that publication is a line on your CV, and that line has no comments attached.

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2. Anon on April 18, 2012 10:11 AM writes...

Who should be blamed? The authors or the editors?

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3. Anonalso on April 18, 2012 10:36 AM writes...

@1 -- +1000. All that matters is pub lines on a CV; To true!

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4. PPedroso on April 18, 2012 11:03 AM writes...

@1 unless there is a retraction...

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5. Anon on April 18, 2012 11:25 AM writes...

@1

And the critique of your pubs shows up when the HR manager does a Google search.

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6. Daen de Leon on April 18, 2012 12:15 PM writes...

You'ver ripped 'em a new azole, Derek ...

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7. Georg-Martin Krapper on April 18, 2012 12:18 PM writes...

As noted (on more than one occasion) in the Crapshoot, I wonder what the reviewers of this manuscript were smoking when they waved this one through. Given this spirited attack on a JMC article, I was suprised that Practial Fragments let dx.doi.org/10.1021/jm201388p off as lightly (practicalfragments.blogspot.co.uk/2012/03/lle-vs-lelp.html) as they did. But don't worry because that's lined up in the cross hairs for the very next Crapshoot. Stay tuned!

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8. marklar on April 18, 2012 12:22 PM writes...

I think this has to do with the increasing amount of crap that's being submitted to JMC (not to mention other journals as well). That's not to say that crap shouldn't be rejected 100% of the time, but add on the perfect storm of a group of reviewers that find that they cannot put in the necessary amount of time to do a proper review, then crap will eventually see its way through. I have been extremely disappointed with the submissions to JMC over the last few years and I am very hesitant to commit to doing a (potentially painful) review of a paper that was prepared with little effort and regard to science. There was 1 paper that I couldn't even read because the grammar was so horrendous (which led to an automatic 'reject manuscript' conclusion). I wish we could screen the paper first without having to commit to doing the review.
I guess I am not all that surprised that this paper made it through.

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9. CBT No7 on April 18, 2012 12:24 PM writes...

As a frequent reviewer for and reader of J. Med. Chem. this does not surprise me at all. There is a large difference in quality at the Associate Editor level. The European editors in particular regularly send out very weak manuscripts for review and then it only takes two soft or rushed reviews.

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10. Anonymous on April 18, 2012 12:34 PM writes...

Had similar experiences as #8 reviewing for JCIM - unreadable English and if you persevere rubbish science lurking underneath. Not surprised this stuff gets through, volume has overwhelmed the filters.

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11. Fries With That? on April 18, 2012 12:41 PM writes...

Does anyone know why they constructed symmetrical dimers? Is there any rationale for that?

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12. Xerxes the Project Manager on April 18, 2012 12:55 PM writes...

I demand publication in your puny journal! You will give tribute to my CV!

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13. MoMo on April 18, 2012 1:21 PM writes...

Another reason to cancel my subscription to JMC!

Spineless jellyfish reviewers!

Lets get these electronic journals going while the Dinosaur dies of a Thousand cuts!

Benzimidazoles are evil molecules anyway, with their evil ways!

I've seen many-a-scientist suffocate in their own feces because of these molecules- Add these new ones to the List!

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14. Curious Wavefunction on April 18, 2012 2:47 PM writes...

For me the biggest merit of JMC over the last few years has been the reviews and perspectives. Everything else I look at through a jaundiced eye; very rarely does the light shine through. I also don't know if I am the only one who gets the feeling that many more consequential (for drug research) papers were published in the journal in the 80s and 90s than in the 2000s.

Also, I haven't read the paper but it's not necessary for high MW compounds to always translate into high LE. Most PPI inhibitors have pretty low LEs and by now it's becoming clear that you can get potent PPI inhibition even if LEs are low. Jim Wells had an article about this in Nature in 2007.

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15. Path on April 18, 2012 5:15 PM writes...

Is it always the reviewers fault? I think the editors have at least a little responsibility (lord knows I wouldn't want to be an editor though!) - I reviewed a paper for JMC a while back which had micro's listed with 0.42 EtOAc and 0.25 MeOH reported, I pointed out that this was pretty meaningless but it got published that way anyway. My reaction was to question whether it was worth the effort if no-one cares to read the review. Spending a couple of hours which could have been used in a more worthwhile pursuit seemed an exercise in futility.

But then again the last paper I reviewed for JMC (this year) had a crude NMR of a reportedly unstable compound as the sole piece of analytical data in the entire manuscript. Wonder if that one will be published regardless? Only time will tell.

BTW Does anyone think that communications should really exist anymore for organic/medicinal chemistry? Sure they make more money for the publlishers and "learned societies" but short full papers (with full characterisation of all compounds) do the job and don't take any longer to write, how many results need to be rushed into press these days? Just the sodium hydride oxidations I guess...

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16. Anonymous on April 18, 2012 7:19 PM writes...

@ #14 - The only reason that the Perspectives remain great versus some of the schlock articles is that Bill Greenlee presides over the former. So there's at least one very good scientific mind taking the time to make sure some part of J Med Chem remains worth reading.

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17. Pformer Pfarma Pfellow on April 18, 2012 7:23 PM writes...

WOW..... I always take the responsibility as a reviewer to heart, but I know that many do not. For communications with limited experimental details it may well be difficult to adequately judge the science, but for any paper with a really unexpected result I would push back with questions that should be answered before a somewhat surprising result (or a poorly documented result) gets published. Or, as in the present example, a question of "what were you thinking and why should we publish this?".

I have seen it all as a reviewer. A few examples:

A paper with a perfectly acceptable synthetic scheme and a good description of the work. Everything looked perfectly plausible, but..... If you followed the experimental details, you realized that the authors somehow managed to drop an entire methylene group (CH2) from the structure of their intermediate as it passed from one experimental to the next. This was a cut and paste job from a variety of sources.

There was the submission that couldn't manage any combustion analysis on any of the intermediates and chose to submit high resolution MS data. The fact that many of the results were spot on to the theoretical results and the rest were within two or three in the final decimal place appeared great unless one compares that to personal experience and asks a Mass Spec colleague what would result from multiple runs on a standard over several days. Further examination of the experimental details revealed many more problems. A red flag on the too good to be true MS results exposed the entire charade..

One of my favorites resulted in a personal letter from the editor of JMC (after an initial review and response to a rebuttal) thanking me for helping to keep some bad science out of the Journal. There were numerous issues here, including things such as dividing by zero to generate a data point and relying on a calculator (not a knowledge of significant figures) to round off fractions to reach a significance value of 0.5 (0.49 was deemed insignificant and 0.5 was significant, I kid you not). This was a typical two-fold dilution scheme. Many, many more problems with this one, but this demonstrates the problem.

The "Devil is in the Details" and it takes a thorough reading (maybe several) of the manuscript to reach a valid conclusion on the quality of the science.

I agree with other posters that all Editors have accepted a lot of responsibility for the quality of what gets into journals. However, they can't read every submission and need to rely on their list of reviewers. The buck actually stops there. We all know that Editors cannot devote enough time to every manuscript to give it critical evaluation. They rely on their staff of reviewers to do the leg work on a smaller number of manuscripts.

That said, if a given Editor or reviewer has a track record of allowing junk science into print they should be removed from their positions. Often serving as an editor or reviewer is listed on a resume as a marker of recognition in the scientific community that has not been earned.

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18. dear_watson on April 18, 2012 8:16 PM writes...

This sort of paper really upsets me. J Med Chem is the journal of choice for real medicinal chemistry projects - be it industrial or academic.

My group bust our asses writing robust publications but to what end if this sort of manuscript gets through. Its not like its PNAS and their editors choice articles

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19. Studstulous on April 18, 2012 9:23 PM writes...

@ # 16. Very true. A nice shout out for all the hard work that Bill does for JMC.

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20. Anon on April 18, 2012 10:36 PM writes...

I have a paper on converting Pb to Au via enzymatic action.

Very nicely ghostwritten...er, written by my team.

Will it be published in this journal?

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21. TX Raven on April 19, 2012 4:56 AM writes...

C'mon, guys... a bit more self-criticism here.
Seeing the way the quality of most (but not all) Medicinal Chemistry research has been declining over the last few years across the table, this should not come as a surprise.

Consider this a courtesy of the bean-counter running your pharma company.

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22. petros on April 19, 2012 8:28 AM writes...

And there has also been an explosion in the number of Med Chem Journals

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23. weirdo on April 19, 2012 10:28 AM writes...

Nice try TX Raven, but these were academic researchers.

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24. Ben Zene on April 19, 2012 10:33 AM writes...

Damn those Indian / Chinese chemists and their crap research. Oh no, wait a minute.....

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25. frustrated reviewer on April 19, 2012 1:35 PM writes...

I'd have rejected this one too, but this is far from an isolated example and somebody has to be letting them all in. I've rejected papers from J Med Chem, explaining to the authors why their results were crap and begging them not to submit it anywhere else, only to see it in print in Eur J Med Chem a few weeks later.

There's a lot not to like in this paper, and the quality of the modeling especially is hopeless, but to give these guys some credit they at least tried to generate the data they should. Fig 3 shows that their horrible compound competes with NADPH, which should rule out the non-competitive modes of action mentioned in the fragment blog link above. (OK, so I'm not convinced their lines really fit their error bars, but at least they tried). And they also tried to generate enzymological stoichiometry data. I'm reminded of papers out there reporting supposedly allosteric kinase inhibitors, which don't usually bother with any of that boring mechanistic stuff, yet still seem to get published and unquestioningly believed.

I don't like making an example of a single paper but if whoever reviewed the article reads this blog, perhaps they'd like to chip in to justify their decision?

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26. Dr Doom on April 19, 2012 2:18 PM writes...

The problem for most of the full paper journals is that the industrial medicinal chemists are a) far fewer in number and b) not working in the same way. Full characterisation of intermediates is expensive and completely unnecessary most of the time. I don't think I ran a CHN in the last ten years of my drug discovery career and that included a program that produced a commercial drug. Apart from the tox batches of development compounds, there is very little craft involved in compound characterisation anymore. So fewer full papers get written and far more communications. Really, only academics can afford to fully characterise everything and so publish full papers, and I'm afraid on average they know about as much about drug discovery as these guys appear to have done. So the quality of full papers continues to go down the drain.

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27. D.J. on April 19, 2012 9:34 PM writes...

Has anyone brought up Rejecta Mathematica yet, in regards to these whoppers of papers? Look at it here: http://math.rejecta.org/

Basically, it's a free journal that publishes papers that were rejected by peer review, but nonetheless may be interesting.

Is there anything like that in chemistry? Should there be?

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28. frustrated reviewer #2 on April 20, 2012 1:53 AM writes...

After reviewing for JMC and JCIM now, I see the problem pretty clearly. The editors rubber stamp stuff. There were grammatical, spelling and downright idiotic scientific flaws in some of the papers i've seen. i stamped all papers with accept - major revisions but they come out WITHOUT being sent back to me in pretty much the exact form i read. from now on this shit gets stamped REJECT and after that i quit reviewing for that editor.

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29. Liz Howell on April 25, 2012 12:24 PM writes...

Dear Teddy Zartler and Derek Lowe,

I was made aware of your blogs on the Bastien et al. paper (April 18th, How do these things get published? & April 17th, Sometimes your compound sucks). I am an enzymologist and I was one of the reviewers of the paper. I would like to respond to your comments.

I have worked on DHFR since the 1980s. You may perhaps be unaware, but there are 2 different types of DHFRs. The chromosomal DHFR is the target of many drug design efforts and is the more well-known enzyme. A protein conferring resistance to trimethoprim, typified by R67 DHFR, was identified in the 1970s. This R-plasmid encoded DHFR (a type II DHFR) has an entirely different scaffold than the chromosomal DHFRs. I wonder if you thought the Bastien et al. paper was describing drug design efforts for the chromosomal DHFR and this misunderstanding is at the root of your concern? For example, Dr. Zettler used the term "mutant DHFR" in his post. Is an apple the same as a mutant orange? To me, R67 DHFR and chromosomal DHFR are like apples and oranges. While these 2 DHFRs catalyze the same reaction, they have different protein folds, different oligomerization states, different active sites (R67 has a single active site pore while chromosomal DHFR has a typical binding cleft) and the enzymes use different transition states (endo vs exo).

FYI, I am attaching a pdf file showing the 2 different structures and a Table comparing the binding constants and active site volumes of the 2 enzymes (emailed to Drs. Lowe & Zartler).

A few observations about R67 DHFR (I am happy to provide citations supporting these data if requested):

-R67 DHFR is a homotetramer and each monomer has a fold that is related to an SH3 domain.

—The R67 tetramer has exact 222 symmetry and a SINGLE active site pore.

—For each cofactor (or substrate) binding site in R67 DHFR, there must be four related sites from the symmetry. However a total of 2 ligands bind per pore, either 2 substrates, 2 cofactors or 1 molecule of each. Only the latter is productive and results in catalysis.

—The classical chromosomal DHFR inhibitors (trimethoprim & methotrexate) do not inhibit R67 DHFR very well (Ki values of 150mM and >500mM respectively).

The above observations (& others) lead to the hypothesis that R67 DHFR has a promiscuous binding surface that can accommodate both ligands. The 222 symmetry imposed on the single active site pore of R67 DHFR is utilized by Bastien et al. in their drug design process as they construct "dimeric" ligands. Again, I wonder if the bloggers did not realize a different DHFR was targeted, as for example, Dr. Lowe says "The authors string these things together into huge dimeric molecules, apparently because they think that this is a good idea, but they get no data to support this hypothesis at all." The hypothesis of Bastien et al regarding symmetry related binding sites comes from the previous crystal structures of the R plasmid enzyme, by stoichiometries derived from time resolved fluorescence and ITC binding studies and by the ability of R67 to catalyze a transhydrogenase reaction (albeit weakly).

With regard to the bloggers comment on electon density interpretation, it is the 222 symmetry that makes it difficult to deconvolute electron density of crystal structures describing bound complexes in R67 DHFR, please see the attached figure of the symmetry problem in this enzyme.

In regards to my review of the paper, I read the paper carefully and wrote 2 pages of comments in my initial review. I also read the revised manuscript. In my opinion, the paper was a first step in the design of an inhibitor that would target this unusual binding site and have some specificity for the R67 DHFR vs. the chromosomal DHFR. To my knowledge, this is the first drug design effort to target R67 DHFR activity. I stand by my decision, the paper is worthy of publication.

Sincerely, Liz Howell, Professor, Biochemistry, Cellular & Molecular Biology Dept., University of TN, Knoxville, TN

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