Tag: The Scientific Literature
Two For One Sale
February 19th, 2010, No Comments
A double complaint this morning, and both from the same literature item – if I were charging anything for the blog, I’d say that it’s delivering value for the money. At any rate, the first kvetch is something that I know that many chemists have noticed when reading more biology/medical-oriented journals. You’ll see some paper that talks about a new compound that does X, Y, and Z. It’ll be named with some sort of code, and they’ll tell you all about its interesting effects. . .but they don’t get around to actually telling you what the damned stuff is.
As I say, this is a chemist’s complaint. Many biologists are fine stipulating that there’s a compound that will do these interesting things, because they’re mostly interested in hearing about the interesting things themselves. It could just be Compound X as far as they’re concerned. But chemists want to see what kind of structure it is that causes all these publication-worthy results, and sometimes we go away disappointed.
Or we have to dig. Take this PNAS paper on a broad-spectrum antiviral compound, LJ001. It looks quite interesting, with effects on a number of different viral types, and through a unique mechanism that targets viral membranes. But what is it? You’ll look in vain through the whole paper to find out – that compound is LJ001 to you, Jack. You have to go to the supplemental material to find out, and to page 10 at that.
And that brings up the second complaint. LJ001 turns out to be a rhodanine, and regular readers will note that earlier this month some time was spent here talking about just how ugly and undesirable those are. It’s very, very hard to get anyone in the drug business to take a compound in that class seriously, because they have such a poor track record. Looking over the small SAR table provided, I note that if you switch that thioamide group (the part that the chemists hate the most) to a regular amide, turning the thing into an thiazolidinedione, you lose all the activity.
TZDs aren’t everyone’s favorite group, but at least they’ve made it into marketed drugs. Rhodanines are no one’s favorite group, and it would be a good thing of the authors of these papers would realize that, or at least acknowledge it if they do. It’s not an irrational prejudice.
Who Follows These Things?
February 12th, 2010, No Comments
My schedule is all over the place today – events at my kids’ school, new projects at work, etc. But I do want to put a quick question out to people: I keep seeing various scientific journals, etc. proudly advertising that they’re on Twitter, Facebook, etc. So, does anyone get any use out of that? I can’t say that I do, but perhaps I’m just set in my ways, if reading journals by RSS feeds can be called “set in my ways”.
I’m willing to be set straight on this, but whenever I see these logos and notices, I can’t help but see some editorial meeting that I imagine went on. “Look, everybody’s on Twitter, says one person around the table. “Well, I’m not,” says an editor, “and I can’t for the life of me figure out why I should be. Won’t we look idiotic ‘tweeting’ at people, or whatever it is?” “Did I mention that it won’t cost us anything to get all Web 2.0-ed up?” says the first guy, and the motion is carried. . .
Another New Med-Chem Journal
February 11th, 2010, No Comments
I should also note that the Royal Society of Chemistry is starting its own med-chem communications journal. MedChemComm. Along with the new ACS journal, this now means that medicinal chemists have more places to publish their work than ever before.
Which is a bit of a sour thought, considering that the number of industry-employed medicinal chemists has been dropping for several years now, and the end does not appear to be in sight. We’ll see how this affects the publishing world (admittedly, a minor worry). In the short term, people are probably trying to make their patent and publication records look as impressive as possible, so I would think that fewer and fewer publishable results are sitting around in desk drawers. In the long term, though, are we going to see fewer papers in general? (Or failing that, more from academic labs?)
Polluting the Literature with PAINs
February 8th, 2010, No Comments
There’s an article out from a group in Australia on the long-standing problem of “frequent hitter” compounds. Everyone who’s had to work with high-throughput screening data has had to think about this issue, because it’s clear that some compounds are nothing but trouble. They show up again and again as hits in all sorts of assays, and eventually someone gets frustrated enough to flag them or physically remove them from the screening deck (although that last option is often a lot harder than you’d think, and compound flags can proliferate to the point that they get ignored).
The larger problem is whether there are whole classes of compounds that should be avoided. It’s not an easy one to deal with, because the question turns on how you’re running your assays. Some things are going to interfere with fluorescent readouts, by absorbing or emitting light of their own, but that can depend on the wavelengths you’re using. Others will mung up a particular coupled assay readout, but leave a different technology untouched.
And then there’s the aggregation problem, which we’ve only really become aware of in the past few years. Some compounds just like to stick together into huge clumps, often taking the assay’s protein target (or some other key component) with them. At first, everyone thought “Ah-hah! Now we can really scrub the screening plates of all the nasties!”, but it turns out that aggregation itself is an assay-dependent phenomenon. Change the concentrations or added proteins, and whoomph: compounds that were horrible before suddenly behave reasonably, while a new set of well-behaved structures has suddenly gone over to the dark side.
This new paper is another attempt to find “Pan-Assay Interference” compounds or PAINs, as they name them. (This follows a weird-acronym tradition in screening that goes back at least to Vertex’s program to get undesirable structures out of screening collections, REOS, for “Rapid Elimination of, uh, Swill”). It will definitely be of interest to people using the AlphaScreen technology, since it’s the result of some 40 HTS campaigns using it, but the lessons are worth reading about in general.
What they found was that (as you’d figure) that while it’s really hard to blackball compounds permanently with any degree of confidence, the effort needs to be made. Still, even using their best set of filters, 5% of marketed drugs get flagged as problematic screening hits – in fact, hardly any database gives you a warning rate below that, with the exception of a collection of CNS drugs, whose properties are naturally a bit more constrained. Interestingly, they also report the problematic-structure rate for the collections of nine commercial compound vendors, although (frustratingly) without giving their names. Several of them sit around that 5% figure, but a couple of them stand out with 11 or 12% of their compounds setting off alarms. This, the authors surmise, is linked to some of the facile combinatorial-type reactions used to prepare them, particularly ones that leave enones or exo-alkenes in the final structures.
So what kinds of compounds are the most worrisome? If you’re going to winnow out anything, you should probably start with these: Rhodanines are bad, which doesn’t surprise me. (Abbott and Bristol Myers-Squibb have also reported them as troublesome). Phenol Mannich compounds and phenolic hydrazones are poor bets. And all sort of keto-heterocycles with conjugated exo alkenes make the list. There are several other classes, but those are the worst of the bunch, and I have to say, I’d gladly cross any of them off a list of screening hits.
But not everyone does. As the authors show, there are nearly 800 literature references to rhodanine compounds showing biological effects. A conspicuous example is here, from the good folks at Harvard, which was shown to be rather nonspecifically ugly here. What does all this do for you? Not much:
“Rather than being privileged structures, we suggest that rhodanines are polluting the scientific literature. . .these results reflect the extent of wasted resources that these nuisance compounds are generally causing. We suggest that a significant proportion of screening-based publications and patents may contain assay interference hits and that extensive docking computations and graphics that are frequently produced may often be meaningless. In the case of rhodanines, the answer set represents some 60 patents and we have found patents to be conspicuously prevalent for other classes of PAINS. This collectively represents an enormous cost in protecting intellectual property, much of which may be of little value. . .”
A Modest Literature Proposal
February 3rd, 2010, No Comments
Looking through the latest papers to show up in the Journal of Medicinal Chemistry, this one on BACE-1 inhibitor compounds caught my eye. Perhaps I’m about to be unfair to it. At any rate, I’m going to ask of it something it doesn’t provide: data in something that’s alive. Doesn’t have to be a person, a dog, or even a rat. A cell would do: something with a membrane to cross, with metabolic processes, and with the ability to accept or reject someone’s new compound. Enzymes just have to sit there and take whatever you throw at them; living systems fight back.
I sometimes think that we’d be better served if each of the medicinal chemistry journals were split. In J. Med. Chem.’s case, we would then have the Journal of In Vitro Medicinal Chemistry and the Journal of In Vivo Medicinal Chemistry. The criteria for publishing in the two journals would be exactly the same, except to get into the latter one, you would have at least had to have tried your compounds out on something besides an in vitro assay. Doesn’t mean that they have to have worked – you just have to have looked.
Although the case of compounds with molecular weights of 900 that have four amides and a sulfonamide in them, and are directed against a target in the central nervous system, might still be a bit of a stretch. I supposed what irritates me about this paper is that it starts off talking about Alzheimer’s disease. And that’s natural enough in a study dedicated to finding inhibitors of BACE-1, but the problem is, Alzheimer’s disease occurs in human beings. And these compounds do not look to have much chance of doing anything inside any human’s body. The best I can say for them is that they might give someone else an insight into something that they might be able to do to make something that might have a better chance of working.
Cranky folks like me would probably refer to the latter of my two new journals as just “J. Med. Chem.”, and would refer to the former one by a variety of other easy-to-remember names. I offer this suggestion for free to the scientific publishing community, who will, I’m sure, reciprocate with things of equal value.
Literature Notes
February 2nd, 2010, No Comments
So, now that we’re in 2010, the journal that introduced the whole idea of a graphical abstract to organic chemistry (Tetrahedron Letters) has finally started including them in their RSS feed. That’s how I read journals these days, and I think I have a lot of company, so I’m grateful that they got around to it.
And on another literature note, I wanted to mention that I’ve accepted an invite to the editorial advisory board of the new ACS journal ACS Medicinal Chemistry Letters. You can tell, I guess, when you’ve been doing this stuff for a while – when I look at the rest of the advisory board, I see people I went to grad school with, people I used to work down the hall from, and so on. The journal has started publishing its first papers; we’ll see how it works out, and how it competes with the other short-form outlet for this sort of work, Bioorganic and Medicinal Chemistry Letters. I promise not to let any anti-Bredt cyclobutenes get past me!
Johnson May Have Been On to Something
January 29th, 2010, No Comments
The crew at Angewandte Chemie has produced another head-shaking pun in one of their latest abstracts. Read only if (1) you know your 1980s music, and (2) you have a high tolerance for wordplay. When I was in Germany, this sort of joke was known as an “eiskalter” and was greeted with shivers.
Johnson May Have Been On to Something
January 29th, 2010, No Comments
The crew at Angewandte Chemie has produced another head-shaking pun in one of their latest abstracts. Read only if (1) you know your 1980s music, and (2) you have a high tolerance for wordplay. When I was in Germany, this sort of joke was known as an “eiskalter” and was greeted with shivers.
Run It Past the Chemists
January 5th, 2010, No Comments
I missed this paper when it came out back in October: “Reactome Array: Forging a Link Between Metabolome and Genome“. I’d like to imagine that it was the ome-heavy title itself that drove me away, but I have to admit that I would have looked it over had I noticed it.
And I probably should have, because the paper has been under steady fire since it came out. It describes a method to metabolically profile a variety of cells though the use of a novel nanoparticle assay. The authors claim to have immobilized 1675 different biomolecules (representing common metabolites and intermediates) in such a way that enzymes recognizing any of them will set off a fluorescent dye signal. It’s an ingenious and tricky method – in fact, so tricky that doubts set in quickly about the feasibility of doing it on 1675 widely varying molecular species.
And the chemistry shown in the paper’s main scheme looks wonky, too, which is what I wish I’d noticed. Take a look – does it make sense to describe a positively charged nitrogen as a “weakly amine region”, whatever that is? Have you ever seen a quaternary aminal quite like that one before? Does that cleavage look as if it would work? What happens to the indane component, anyway? Says the Science magazine blog:
In private chats and online postings, chemists began expressing skepticism about the reactome array as soon as the article describing it was published, noting several significant errors in the initial figure depicting its creation. Some also questioned how a relatively unknown group could have synthesized so many complex compounds. The dismay grew when supplementary online material providing further information on the synthesized compounds wasn’t available as soon as promised. “We failed to put it in on time. The data is quite voluminous,” says co-corresponding author Peter Golyshin of Bangor University in Wales, a microbiologist whose team provided bacterial samples analyzed by Ferrer’s lab.
Science is also coming under fire. “It was stunning no reviewer caught [the errors],” says Kiessling. Ferrer says the paper’s peer reviewers did not raise major questions about the chemical synthesis methods described; the journal’s executive editor, Monica Bradford, acknowledged that none of the paper’s primary reviewers was a synthetic organic chemist. “We do not have evidence of fraud or fabrication. We do have concerns about the inconsistencies and have asked the authors’ institutions to try to sort all of this out by examining the original data and lab notes,” she says.
The magazine published an “expression of concern” before the Christmas break, saying that in response to questions the authors had provided synthetic details that “differ substantially” from the ones in the original manuscript. An investigation is underway, and I’ll be very interested to see what comes of it.
Why Don’t Chemists Communicate? (Or Do We?)
December 17th, 2009, No Comments
There’s a commentary in the December issue of Nature Chemistry asking why our field has been comparatively slow to adopt web-based technologies like arXiv and GenBank:
“New web-based models of scholarly communication have made a significant impact in some scientific disciplines, but chemistry is not one of them. . .why do similar initiatives in chemistry fail to gain critical mass and widespread usage?”
The article considers several possibilities – among others, that (a) other fields aren’t actually quite as techno-webby as we think they are, or (b) there might be a mismatch between chemistry as a discipline and the current tools, one that isn’t found in some other fields of science, or (c) that there could be just a few defined issues that need to be addressed, then things will take off, or (d) that chemists already have the communication tools that they need, anyway.
The authors point out that technical hurdles can probably be ruled out as an explanation, and in many cases they can also rule out “because no one’s ever tried”. Elsevier, for example, tried to get an arXiv-type preprint server going a few years ago, but that bombed pretty thoroughly (not least, I think, because people were naturally a bit suspicious of such an effort being launched under Elsevier’s banner, and because the ACS journals refused to take manuscripts that had appeared there). Nature has been trying something similar in the last couple of years with Nature Precedings, but I’m not sure if it’s taking off or not. I’ve never really used it myself, if that’s a data point worth mentioning.
One key point that the authors make is that totally new means of communication don’t just pop into existence in a scientific discipline. The ones that catch on tend to build on things that the scientists are already doing. I think that physicists, for example, were already more used to sharing preprints of articles, and that the arXiv server just helped them do that more easily. Chemists, on the other hand Just Don’t Do That, so announcing to them that Now They Can! isn’t enough to bring in participants.
On the same chemistry-is-different front, the commentary also notes that our field has always had an emphasis on making stuff, although they don’t put it quite that way. The computer is not usually the machine that produces our results; it’s just the means by which we keep track of them. And we don’t generate the piles of (sometimes) reusable data that physicists do, so much as we generate new substances and new ways of making and using them. The data are there to show that we did, in fact, make what we said we made. Those piles of data also tend to hold their value much longer than in other fields, too – after all, a compound is a compound, and its NMR spectrum doesn’t change. If you want to know how some class of compounds behave, a paper from fifty years ago (or more) can be a perfectly good place to look.
Also in contrast to the physics community, chemistry is broken up into many smaller units. You’ll never see a chemistry paper with as many co-authors as a high-energy physics paper, because we don’t have to run our experiments on the One Big Machine In the Whole World. It may be that parts of the physics world have basically been forced to collaborate more widely, because that’s the only way to get anything done. We also have a wide range of sub-disciplines, what with physics on one side of us and biology on another, and these all have their own idiosyncracies. (And, of course, many of us work in areas where we basically can’t share some information until we’re good and ready to).
One thing that the whole article doesn’t quite address though, is: what would these wonderful new communication modes be, actually? And how would they improve my research life? Electronic literature searching certainly has, as has the availability of journals online. Electronic notebooks definitely have. What else would? I’m sure that there must be a few things, but I find that some of the Web 2.0 info-heaven visions that people outside the field talk about don’t do much to excite me. It’s like seeing some scientific abstract online, and then noting the little row of social-media icons below it, inviting me to submit the thing to Digg, Reddit, or what have you. Or to go visit the journal’s page on Facebook, of all things. Why I’d do that is something I haven’t quite figured out yet.
But hey, I’m not as much of a Luddite as that makes me sound. I also note this passage from the article (emphasis mine):
An increasing number of scientists have adopted blogging as a means of informal communication. Typicall, the writing style of blogs is conversational, and humorous content gets mixed with posts of a more serious tone. Some blogs are dedicated to educating lay audiences, others aim at an academic discussion, and many are like personal diaries. At this point in time, many science bloggers are assumed to be less than 30 years old, and are primarily journalists, teachers, graduate students, or young researcher. Hardly any established scientists maintain a blog – after all, blogging regularly is very time-consuming. The question remains open whether these will remain fringe phenomena or become part of the mainstream communication in science.
