Ligands From Nothing
Well, nearly nothing. That's the promise of a technique that's been published by the Ernst lab from the University of Basel. They first wrote about this in 2010, in a paper looking for ligands to the myelin-associated glycoprotein (MAG). That doesn't sound much like a traditional drug target, and so it isn't. It's part of a group of immunoglobulin-like lectins, and they bind things like sialic acids and gangliosides, and they don't seem to bind them very tightly, either.
One of these sialic acids was used as their starting point, even though its affinity is only 137 micromolar. They took this structure and hung a spin lab...
Source: In the Pipeline - September 12, 2013 Category: Chemists Tags: Drug Assays Source Type: blogs
A New Version of ChemDraw Mobile
I mentioned ChemDraw for the iPad earlier this year, but the folks at PerkinElmer tell me that they've released a new version of it, and of Chem3D. (They're here and here at Apple, respectively). They've added text annotation, which seems to have been a highly requested feature, adjustable arrows, and a number of other features. Worth a look for the chemist-on-the-go. (Source: In the Pipeline)
Source: In the Pipeline - September 11, 2013 Category: Chemists Tags: Chemical News Source Type: blogs
Merck Does Something. Or Not. Maybe Something Else Instead.
There's some Merck news today, via FiercePharma. First off, their R&D head Roger Perlmutter sat down with some of the most prominent analysts for a chat about the company's direction - and they came out with two completely different stories. Big changes? Minor ones? I wonder if people were taking away what they wanted to hear to confirm what they'd already decided Merck should be doing. Seamus Fernandez, for example, apparently came away saying that he thought a major R&D restructuring was inevitable, but that's what he thought before he sat down. This sort of thing is worth keeping in mind when you hear some Wall St. type...
Source: In the Pipeline - September 11, 2013 Category: Chemists Tags: Cancer Source Type: blogs
Great Papers That Have Been Rejected
A discussion in the lab brought up this topic: there have been, so everyone hears, famous papers in the sciences that were rejected by the first journals that they were submitted to. I believe, for example, that Dan Schectman faced a lot of opposition to getting his first quasicrystal work published (and he certainly got a lot, notably from Linus Pauling, after it came out). To pick one, the original Krebs cycle paper was turned down by Nature, which a later editor called the journal's biggest single mistake. Here are some famous examples from computer science and related mathematics (update: in a parody/spoof paper!) and ...
Source: In the Pipeline - September 10, 2013 Category: Chemists Tags: The Scientific Literature Source Type: blogs
Bring Me More Cute Ring Systems
Here's a paper from the Carreira group at the ETH, in collaboration with Roche, that falls into a category I've always enjoyed. I put these under the heading of "Synthetic routes into cute functionalized ring systems", and you can see my drug-discovery bias showing clearly.
Med-chem people like these kinds of molecules. (I have a few of them drawn here, but all the obvious variations are in the paper, too). They aren't in all the catalogs (yet), they're in no one's screening collection, and they have a particular kind of shape that might not be covered by anything else we already have in our files. There's no reason why s...
Source: In the Pipeline - September 10, 2013 Category: Chemists Tags: Chemical News Source Type: blogs
What To Do About Chemistry Papers That Don't Work?
I wanted to follow up on a point raised in the comments to this morning's post. Reader DJ writes that:
Our lab recently tried to repeat a procedure from a TL methodology paper on the amination of amines to make protected hydrazines. We noticed that the entire paper is wrong since the authors did not analyze the product NMRs carefully, and incorrectly assumed that they were forming the desired hydrazines, rather than the rearranged alkoxyamines. It's a systemic error throughout the paper that renders the entire premise and methodology essentially useless. So our quandry is this: (1) This is clearly not a case of fraud, but...
Source: In the Pipeline - September 9, 2013 Category: Chemists Tags: The Scientific Literature Source Type: blogs
Exposing Faked Scientific Papers
Chemistry World has a good article on the problem of shaky data in journal article, and the intersecting problem of what to do about it in the chemistry blogging world. Paul Bracher's ChemBark is, naturally, a big focus of the piece, since he's been highlighting some particularly egregious examples in the last couple of months (which I've linked to from here).
The phrase "witch hunt" has been thrown around by some observers, but I don't think that's fair or appropriate. In great contrast to the number of witches around (and their effectiveness), faked information in published scientific articles is very much a real thing,...
Source: In the Pipeline - September 9, 2013 Category: Chemists Tags: The Dark Side Source Type: blogs
Making the Bacteria Make Your Fluorinated Compounds
Acetate is used in vivo as a starting material for all sorts of ridiculously complex natural products. So here's a neat idea: why not hijack those pathways with fluoroacetate and make fluorinated things that no one's ever seen before? That's the subject of this new paper in Science, from Michelle Chang's lab at Berkeley.
There's the complication that fluoroacetate is a well-known cellular poison, so this is going to be synthetic biology all the way. (It gets processed all the way to fluorocitrate, which is a tight enough inhibitor of aconitase to bring the whole citric acid cycle to a shuddering halt, and that's enough to...
Source: In the Pipeline - September 6, 2013 Category: Chemists Tags: Natural Products Source Type: blogs
More on Warp Drive Bio and Cryptic Natural Products
At C&E News, Lisa Jarvis has an excellent writeup on Warp Drive Bio and the whole idea of "cryptic natural products" (last blogged on here). As the piece makes clear, not everyone even is buying into the idea that there's a lot of useful-but-little-expressed natural product chemical matter out there, but since there could be, I'm glad that someone's looking.
Yet not everyone looked at the abundant gene clusters and saw a sea of drug candidates. The biosynthetic pathways defined by these genes are turned off most of the time. That inactivity caused skeptics to wonder how genome miners could be so sure they carried the reci...
Source: In the Pipeline - September 6, 2013 Category: Chemists Tags: Biological News Source Type: blogs
CRISPR Takes Off
If you haven't heard of CRISPR, you must not have to mess around with gene expression. And not everyone does, true, but we sure do count on that sort of thing in biomedical research. And this is a very useful new technique to do it:
In 2007, scientists from Danisco, a Copenhagen-based food ingredient company now owned by DuPont, found a way to boost the phage defenses of this workhouse microbe. They exposed the bacterium to a phage and showed that this essentially vaccinated it against that virus (Science, 23 March 2007, p. 1650). The trick has enabled DuPont to create heartier bacterial strains for food production. It al...
Source: In the Pipeline - September 5, 2013 Category: Chemists Tags: Biological News Source Type: blogs
Astex Gets Bought
So Astex, one of the pioneers in fragment-based drug discovery, has been bought by Otsuka for their oncology portfolio. You don't hear people asking "What has all this fragment stuff accomplished?" as much as you used to, but here's another answer: an $886 million dollar buyout.
The president of Otsuka says that they're going to keep Astex's research the way it is:
"Astex's unique fragment-based drug discovery technology and clinical oncology research and development capabilities, born out of the passion of its researchers, exemplify our corporate mottos and belief in "Sozosei (Creativity) and Jissho (Proof through Execu...
Source: In the Pipeline - September 5, 2013 Category: Chemists Tags: Business and Markets Source Type: blogs
Stack Ranking in Pharma: Bad Idea
Steve Ballmer's departure from Microsoft, snidely remarked on here, has prompted any number of "What went wrong?" pieces to appear. One of the key documents, though, is from last year: Kurt Eichenwald's writeup in Vanity Fair. The editorial staff has helpfully illustrated it with a photo of Ballmer himself that's so characteristic of his style that it's liable to give ex-Microsofters the shivering flashbacks.
One of the common themes to all these articles is the company's use of "stack ranking", where you evaluate your direct reports and rank them top to bottom. The bottom performers get hammered, no matter how they might...
Source: In the Pipeline - September 4, 2013 Category: Chemists Tags: Business and Markets Source Type: blogs
More Thoughts on Compound Metrics
Over at Practical Fragments, Dan Erlanson has comments on the Michael Shultz paper that I wrote about here. He goes into details on some of the problems that turn up when you try to apply various compound metrics across a broad range of molecular weights and/or lipophilicities. In the most obvious example, the indices that are based on Heavy Atom Count (HAC) will jump around much more in the low-molecular-weight range, and none of the proposed refinements can quite fix this. And with the alternative LELP measure, you have to watch out when you're at very low LogP values.
Shultz's preferred LipE/LLE metric avoids that prob...
Source: In the Pipeline - September 4, 2013 Category: Chemists Tags: Drug Assays Source Type: blogs
The Myth of the STEM Shortage, In Detail
I see that the IEEE Spectrum has also come out saying that there is no shortage of scientists and engineers. I agree with him, as longtime readers will know. The market for people who do these things does not look like a market facing any kind of shortage:
What’s perhaps most perplexing about the claim of a STEM worker shortage is that many studies have directly contradicted it, including reports from Duke University, the Rochester Institute of Technology, the Alfred P. Sloan Foundation, and the Rand Corp. A 2004 Rand study, for example, stated that there was no evidence “that such shortages have existed at least sinc...
Source: In the Pipeline - September 3, 2013 Category: Chemists Tags: Business and Markets Source Type: blogs
A Drug Delivery Method You Haven't Thought Of
Word came last week that Google Ventures is funding a small outfit called Rani Biotechnology. They're trying to solve a small problem that's caught the attention of a few people now and then: making large protein drugs orally available.
Well, Google has a reputation for bankrolling some long-shot ideas, and any attempt to make proteins available this way is, by definition, a long shot. On Twitter, Andy Biotech sent around a link to this patent, which seems to have some of Rani's approach in it. If so, it's a surprising mixture of high and low tech. The drugs would be administered in a capsule, carefully formulated both ch...
Source: In the Pipeline - September 3, 2013 Category: Chemists Tags: Drug Development Source Type: blogs
