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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 27, 2012

Different Worlds: A Last DHFR Paper Thought

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Posted by Derek

Inspired by a discussion with a colleague, I'm going to take one more crack at the recent discussion here about the J. Med. Chem. DHFR paper. Those of you with an interest in the topic, read on. Those whose interest has waned, or who never had much interest to start with, take heart: other topics are coming.

It's clear that many people were disappointed with my take on this paper, and my handling of the whole issue. Let me state again that I mishandled the biology aspects of this one thoroughly, through carelessness, and I definitely owe this apology to the authors of the paper (and the readers of this site) for that.

Of course, that's not the only arguable thing about the way I handled this one. As I spent paragraphs rambling on about in yesterday's post, there's a chemical aspect to the whole issue as well, and that's what caught my eye to start with. I think one of the things that got me into trouble with this one is two different ways of looking at the world. I'll explain what I mean, and you can judge for yourself if I'm making any sense.

The authors of the paper (and its reviewer who commented here) are interested in D67 dihydrofolate reductase, from a biological/enzymological perspective. From this viewpoint - and it's a perfectly tenable one - the important thing is that D67 DHFR is an unusual and important enzyme, a problem in bacterial resistance, interesting in its own right as a protein with an odd binding site, and for all that, still has no known selective inhibitors. Anything that advances the understanding of the enzyme and points toward a useful inhibitor of it is therefore a good thing, and worth publishing in J. Med. Chem., too.

I come in from a different angle. As someone who's done fragment-based drug discovery and takes a professional interest in it, I'll take a look at any new paper using the technique. In this case, I gave the target much too cursory a look, and filed it as "DHFR, bacterial enzyme, soluble, X-ray structures known". In other words, a perfectly reasonable candidate for FBDD as we know it. Once I'd decided that this was a mainstream application of something I already have experience with, I turned my attention to how the fragment work was done. By doing so, I missed out on the significance of the DHFR enzyme, which means, to people in the first camp, that I whiffed on the most important part of the entire thing. I can understand their frustration as I brushed that off like a small detail and went on to what (to them) were secondary matters.

But here's where my view of the world comes in. As a drug discovery guy, when I read a paper in J. Med. Chem., I'd like to see progress in, well, the medicinal chemistry of the topic. That was the thrust of my blog post yesterday: that I found the med-chem parts of the paper uncompelling, and that the application of fragment-based techniques seemed to me to have gone completely off track. (I havne't mentioned the modeling and X-ray aspects of the paper, as Teddy Z did at Practical Fragments, but I also found those parts adding nothing to the worth of the manuscript as a whoel). The most potent compounds in the paper seem, to me, to be the sort that are very unlikely to lead to anything, and are unlikely to show selectivity in a cellular environment. If the paper's starting fragment hits are real (which is not something that's necessarily been proven, as I mentioned in yesterday's post), then it seems to me that everything interesting and useful about them is being thrown away as the paper goes on. From the other point of view, things are basically the opposite - the paper gets better and better as the compounds get more potent.

But here's where, perhaps, the two viewpoints I spoke of earlier might find something in common. If you believe that the important thing is that selective inhibitors of D67 DHFR have finally been discovered, then you should want these to be as potent and selective as possible, and as useful as possible in a variety of assays. This, I think, is what's in danger of being missed. I think that a fragment-based effort should have been able to deliver much more potent chemical matter than these compounds, with less problematic structures, which are more likely to be useful as tools.

I'll finish up by illustrating the different angles as starkly as I can. The authors of this paper have, in one view of the world, completed the first-ever fragment screen against an important enzyme, discovered the first-ever selective inhibitors of it, and have published these results in a prestigious journal: a success by any standard. From my end, if I were to lead a drug discovery team against the same enzyme, I might well see the same fragment hits the authors did, since I know that some of these are in the collections I use. But if I proceeded in the same fashion they did, prosecuting these hit compounds in the same way, I would, to be completely honest about it, face some very harsh questioning. And if I persevered in the same fashion, came up with the same final compounds, and presented them as the results of my team's work, I would run the serious risk of being fired. Different worlds.

Update: Prof. Pelletier sends the following:

I certainly have been following this with interest, and learning much from it – not just science.

Throughout the week, I have appreciated your civil tone – many thanks. I willingly accept your apology, just as I accept the constructive criticism that will improve our future work. I think your ‘two-worlds’ point of view smacks of truth. The bottom line from my point of view is that I’m open to collaboration with a real fragment library: if anyone is interested in making this better, they should contact me. I’d be delighted to work with more than what can be scavenged from neighbouring labs in an academic setting.

Your bloggers’ response to this come-and-go was fascinating: the process was admired to an extent that surprised me. A number of responders point out that there are currently few occurrences of open exchange on these blogs and – sorry to disappoint hard-core bloggers – it does not endear me to the blogging process. I don’t blog because I can’t stand anonymous, frequently disrespectful and sometimes poorly researched comments. I nonetheless hope that this will open the door to a more transparent blogging process in the long run.

For any who care, I am brave, not at all desperate, and definitely a woman. ; )

If you feel any of this would be of interest for your blog, please feel free to post. Thanks for seeing this through rather than shaking it off.

Comments (21) + TrackBacks (0) | Category: Academia (vs. Industry) | The Scientific Literature


COMMENTS

1. Rick Wobbe on April 27, 2012 8:13 AM writes...

I still think this was a healthy discussion, partly for what it illustrates about the science involved, but equally importantly, for what it illustrates about the psychology, sociology and general humanity of even the hardest of "hard" sciences like medicinal chemistry and/or chemical biology. This type of discussion, including the misapprehensions, finicky tastes and prickly personalities takes place thousands of times every day in labs, conference rooms, lunch rooms and coffee rooms everywhere, often (usually?) with much less civility than the principals showed us here. It's gonna happen, and it should happen, in interesting research. Thanks for modeling the process handled as well as can be done given our human flaws.

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2. Rick Wobbe on April 27, 2012 8:39 AM writes...

While we're on the general topic... Derek, how about an update on what's transpired since you corresponded with the authors and editors on the buckyball lifespan extension paper? Even no news would be news.

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3. weirdo on April 27, 2012 10:49 AM writes...

Well, speaking as but one of the anonymous horde, I congratulate both you and Prof. Pelletier for taking this where it really needed to go -- a respectful debate on the merits of a scientific paper; an appreciation for the differences in expertise and motivation of disparate parties; and at least the offer of future collaboration to improve the understanding of the SCIENCE even further.

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4. David Formerly Known as a Chemist on April 27, 2012 11:21 AM writes...

Derek, academia and industry are indeed two different worlds, as many on your blog have noted for years (yourself included). I've got to say, though, that your original post yesterday and your follow-up today were overly snarky. Your last two paragraphs today (before the inclusion of Professor Pelletier's update) read, once again, as a direct condemnation of her lab's research results.

"I think that a fragment-based effort should have been able to deliver much more potent chemical matter than these compounds, with less problematic structures, which are more likely to be useful as tools." - You've never encountered an intractable target before that fails to yield good hits or attractive lead structures? Ever worked on a phosphodiesterase? Remember, of course, these results were produced by a lab with limited resources, without access to the screening library of a pharma company. I've seen worse crap come out of corporate screens (you probably have too). Remember combichem?

"And if I persevered in the same fashion, came up with the same final compounds, and presented them as the results of my team's work, I would run the serious risk of being fired." - Oh my. There's no two ways to read this. Your results are crap, professor, and I'd get canned if I presented them as my results. Cheap shot.

Pelletier's paper is the result of students learning a medicinal chemistry technique in an environment that isn't a pharma company. Recognize it for what it is rather than trashing it for what it isn't.

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5. Derek Lowe on April 27, 2012 11:47 AM writes...

David, I have to call 'em the way that I see 'em, or there's no point in having a blog. If this paper had been sent to me for review, I would not have let it through until major revisions had been made.

And it's worth noting that the hits that came out of screening in this case aren't necessarily crappy at all (although they need more follow-up, as do all primary fragment hits). It's the direction that things took after that which gave me problems.

There is, as far as I know, no "Journal Of Students Learning Medicinal Chemistry". . .

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6. Hap on April 27, 2012 11:57 AM writes...

I'm sorry, Dr. Pelletier, if I was too harsh about your library. I don't think it's good but I was harsher than I should have been.

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7. NJBiologist on April 27, 2012 12:07 PM writes...

"'The bottom line from my point of view is that I’m open to collaboration with a real fragment library: if anyone is interested in making this better, they should contact me.'"

For my money, this is the best part of the whole exchange.

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8. anon2 on April 27, 2012 12:13 PM writes...

4, David Formerly....: well said.

All very entertaining, if not a bit sad. The primary blog author having placed himself in a deep hole, now attempting to get out with a stream of logic and words where he ultimately is digging harder & faster. The hole simply gets bigger, deeper.....

One thing to point out from yesterday's posts: anonymity can allow for participation in such expression and debate. For example, many employers (for right or wrong, another issue that can be extensively discussed), would not tolerate "line-technical staff" to participate in expression of such polarizing personal opinions that could be taken as an expression of the employer's position and possibly effect ongoing or future collaborations where no upfront denial or disassociation can guarantee perceptions in conflict of interest or provide a legal separation and avoid potential litigation. At least one company of which I am aware actually blocks this and other "opinion" sites from company internal web-site access! This is being written to put in perspective the situation with many hard working researchers who want to continue in their current positions without extra local, political pressures, unneeded stress and "future" risks to their situations in today's tough job market. I'm quite sure many readers and contributors to this blog will agree.

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9. Derek Lowe on April 27, 2012 12:21 PM writes...

Anon2, hey, logical streams of words are what I offer around here, and pretty much all I keep in inventory. But I agree with you on anonymity. I think it has real disadvantages, but the benefits still outweigh it. For better or worse, though, I put my name on everything.

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10. Chrispy on April 27, 2012 12:39 PM writes...

This has been a very useful and informative exchange. Entertaining, too! I like how everyone can remain civil and disagree. For what it's worth, my take on the article was very aligned with your original one, Derek, and it is really eye-opening to see parts which I missed completely.

And Dr. Pelletier, thanks for being a good sport!

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11. Anonymous on April 27, 2012 1:42 PM writes...

I want my bucky balls bucky balls bucky balls bucky balls...

What's up with those bucky balls bucky balls bucky balls bucky balls???

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12. Liz Howell on April 27, 2012 3:21 PM writes...

All,

It has taken me awhile to gain equanimity in my life (I’m 61). However when I saw the first blog plus comments, I still reacted to the "demolish" comment and the "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." I found these comments to be very different from an invitation to a respectful dialogue. While I was able to identify myself as one of the reviewers of the paper & inquire in a reasonably balanced fashion if the issue was a misunderstanding about which DHFR was involved, I wonder about the impact of the initial blog on any student authors of the Bastien et al. paper. How did they react? I ask as I have been co-teaching a Science ethics journal club for 2 years and the topic the students find most interesting is mentorship. They react to inequalities in power, feeling vulnerable as students.

I do appreciate that Dr. Lowe has been willing to continue the dialogue and that the tone of the posts has changed. Liz Howell, UTK, Biochemistry

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13. MolecularGeek on April 27, 2012 4:59 PM writes...

I am also glad to see the positive tone that has generally prevailed in this discussion. There is one particular concern that I have over this work that may be somewhat unique, but I fear not.

There have been multiple posts, discussions, and heated exchanges here over the years over the viability, significance, and meaning of academic work in drug discovery. As someone currently in that setting, I have seen enough comments that read as "go back to basic science and leave drug discovery to organizations that have the resources and facilities for it" to realize that the concept is not universally well-received. No matter how novel the target is, I have to agree with Derek's concern about the nature of the library used, and the suitability of their final product for chemical elaboration. I have no doubt that his initial gut reaction, either right or wrong, was probably repeated by many other industrial scientists upon skimming this paper. And that just makes it harder for the rest of us who are trying to build the credibility of our efforts in academic drug discovery. I don't mean to sound as if I am dismissing the importance of the target or, heaven forfend, minimizing the importance of students starting out on manageable projects, but this is something that bothered me when I read Derek's first post on this paper and that hasn't really left me at all through the followups.

MG

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14. pharmadude on April 27, 2012 8:30 PM writes...

A lot of discussion about a not very good paper. Dr. Pelletier is clearly not an expert in the area of fragment based drug discovery.

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15. Howie on April 27, 2012 11:31 PM writes...

@Liz Howell-Thanks for your initial post on your reading of the paper as a referee. I am surprised that, while others, including Derek, continue to assert that they would not have allowed the paper to be published, have not responded to your clearly written and argued post the other day. Much negativity in this blog, and especially on the Pelletier paper was directed at the publication and review process. I, for one, am glad that people like you (responsible, informed and considerate) are assigned as reviewers, and not some of those who have commented on the paper and the authors. I don't agree that the tone was very civil in all comments, despite the many self-congratulatory claims from those active on the blog. There was negative impact to real people: students, professors and reviewers. This seems to be lost on Derek and many who piled onto the attack of this paper. You put a face on what is good about peer review, and I found your courage and professionalism inspiring. Thank you.

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16. RM on April 28, 2012 2:51 PM writes...

pharmadude@14 - She never claimed she was. (Did you read the Derek's blog entry (i.e. the one you're posting under) about the two different perspectives?)

On Prof. Pelletier's addendum - "Frequently disrespectful and sometimes poorly researched comments" aren't any better when they're posted by people who attach their name to them. A jerk who publicly stands behind his words is still a jerk.

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17. jackgg on April 28, 2012 3:09 PM writes...

These things happen these days. Professors have to publish whatever could count as a paper and help them get fund. If immatured work have been published, it is the direct fault of the reviewers obviously. Jackgg

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18. pharmadude on April 29, 2012 10:55 AM writes...

RM@16. I think when you publish a paper on a topic, particularly in a leading journal, then you're claiming to be an expert in the field. There are a few different authors on the article, one of them must be claiming to be the expert in fragment based drug design? I do not know which one however.

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19. disagree on April 29, 2012 11:50 AM writes...

@Pharmadude,I disagree about your comment " I think when you publish a paper on a topic, particularly in a leading journal, then you're claiming to be an expert in the field." If this was the case, no junior PIs will be able to publish in reputable journals such as JMC, no matter how novel and successful their research are. Sounds too pessimistic, don't you think?

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20. pharmadude on April 29, 2012 6:35 PM writes...

@disagree. You're defining the term 'expert' as equivalent to 'world's leading authority'. Any professional chemist who has worked as part of a fragment discovery group can claim to be an expert in fragments as part of their resume.

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21. MoMo on May 1, 2012 8:27 PM writes...

Arghh! Its the curse of the Benzimidazoles!

24/40 on a Dead Man's Chest!

Lest you be warned again! Stay Away from the Most Evil of Molecules!

You've been Warned All You Whining-Sniveling Chemists!

Look What they have done to Mere Mortals!

They have turned you into Spineless Jellyfish!

Now walk the Plank! All of You!
Arghhh!

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