A Chemistry (Chemical) Blogs' Aggregator
February 8th, 2010
Well, I have no particular need to make azo-linked compounds (see this morning's post for one reason!). And I have to say, although it's mechanistically interesting, I definitely feel no desire to make them by combining a hydroperoxide and a diazonium salt in one pot. This is not a moment destined to take its place alongside the legendary invention of the chocolate/peanut butter cup.
Categories: Uncategorized
February 8th, 2010
Just got home after a massive day at #asc2010. Though I’m exhausted I’m feeling too excited to sleep, so instead I’ll give you my blow by blow account of the conference.
Welcome session
The day opened with a welcome from an Aboriginal elder who was not at all interested in science (actually, she said she hated it in school), but was nonetheless entertaining and welcoming. Later the minister did the “official” opening of the conference and also unveiled a new report on science communication policy called Inspiring Australia, which is in my bag to be tackled in all the free time I have. After opening the conference, he left, which was a shame. Guess he’s a busy man.
Plenary session #1
What is a plenary anyway? This was a panel discussion on the challenges for science communication with speakers from some major organisations, the NHMRC (National Health Medical Research Centre), the ARC (Australian Research Centre) and CSIRO. On the whole, it was great to hear from directors and managers from those kind of organisations, but a lot of it was beyond me… We talked a lot on what we SHOULD be doing for science communication strategically, but it seemed to lack that follow through of funding and prioritisation that you need in a business. Eh. It was definitely interesting, but not terribly relevant.
Sub-plenary
Described in the program as “the future of science reporting” I was really disappointed to find the session only heard from print media reporters… sure, it was interesting to hear their ideas about the future of magazines and newsletters, but the future of science reporting encompasses radio, television, blogs and STACKS more than print media. Plus one of the speakers actually said that newspapers were more reliable and accurate then blogs. Uh huh. Sure. Newspapers are accurate eh? Have you heard about Bad Science? And you think blogs are inaccurate? Have you even TRIED reading The Loom and Not Exactly Rocket Science? I’m sorry, but if you think blogs are bad and newspapers are good, you’re living in the past and it’s time to update.
Session Three – Denialists, sceptics and quackery
The panel included the president of the Australian Skeptics. It was described in the program as TACKLING these kind of viewpoints. Damn it if we didn’t just describe the damn problem in a self-rightous way! Yes, I KNOW homeopathy, chiropractics and the anti-vaccine lobbyists say some whacko stuff and have a scary amount of followers, but how do we REACH those believers and talk to them about the actual science? I’m already aware of the problems, I want to talk about solutions, and sadly we barely hit the very tippy top of the iceberg in this session. I’d like to come back to that idea later in this blog while I’m still in swashbuckling scientist mode.
Session Four – Freelancing
“Be a media slut until you can get paid!” No… I actually found this professional development session really worthwhile. Their “get published anyway you can” approach was, I think, good advice to someone starting out. I am certainly keen to start writing for anyone and everyone to garner up a folio of clippings! Ideas included writing for a uni newsletter, contributing to refereed websites, writing for local newsletters, and getting involved with community TV and radio. Yep, I can do that.
Session Five – Determining Junk Science
Our speaker was like Ben Goldacre for peer reviewed journals. OMG the things he said were scary! Over 50% of published journals mess up their statistics or do not explain their error bars! That’s just bad science! Worse than that, a basic knowledge of Poisson distribution should show reviewers when results have been fudged, because the given standard distribution is insanely narrow for the cell counts they are doing. Worst of all are the western blots, who under pretty rudimentary scrutiny by increasing contrast are shown to be cut and pasted, in some cases duplicated or mirror images used later on – basically results completely fabricated and falsified to create results that are flawed in their flawlessness. This session was an eye-opener, and it was good to remember the old stats homework and find some use for them.
Overall though, a conference is about networking, and I met some great people who are doing fantastic things with science communication. If you met me at the conference and scored a business card (yes, I have those now!) then it was lovely to meet you. It was also great to hang out with the gang from the RiAus, who were my SciComm pals in bonny Adelaide and are still doing some amazing things there. Wish I could attend the conference Tuesday and Wednesday, but sadly study calls and I must answer the siren song of commitment.
Categories: Uncategorized
February 8th, 2010
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. . ."
Categories: Uncategorized
February 7th, 2010
Celastrol, derived from trees and shrubs called celastracaea, (Thunder of God Vine) has been used for centuries in China to treat symptoms such as fever, chills, joint pain and inflammation.Celastrol has been shown to possess antioxidant, anti-inflammatory activities. The same compound has been tried for Alzheimer's disease and anticancer activity also.
Categories: Chemistry
February 6th, 2010
Categories: Chemistry
February 5th, 2010
Categories: Chemistry
February 5th, 2010
There's a nice review on GPCRs and their continuing challenges in the British Journal of Pharmacology this month. The authors focus on both structural and functional challenges in the characterization of this most important class of signaling proteins. As is well-known, drugs targeting GPCRs generate the highest revenue among all drugs. And given their basic roles in signal transduction, GPCRs are also clearly very important from an academic standpoint. Yet there is a wall of obstacles confronting us.The concept of a receptor existing in a simple pair of active and inactive states (R and R*) is no longer sufficient to explain the observations of pharmacology. Agonists vary considerably in their efficacy and how this relates to the bound conformational states is unclear. A partial agonist with 50% efficacy could fully activate 50% of the receptors or could activate 100% of the receptor by 50%. Alternatively, a partial agonist might stabilize a different form of the receptor to a full agonist state and this different conformation might activate the G protein with a lower efficiency. The study of rhodopsin suggests that activation of the receptor involves the release of key structural constraints within the E/DRY and NPxxY regions. Energy provided by agonist binding must be sufficient to break these constraints and stabilize the new active conformation. In the case of rhodopsin, whether this transition is complete or partial depends on the chemical nature of the ligand (Fritze et al., 2003). The retinal analogue 9-demethyl-retinal is a partial agonist of rhodopsin which only poorly activates G protein in response to light. Spin-labeling studies (Knierim et al., 2008) suggest that in the presence of this ligand, only a small proportion of receptors are in the active conformation equivalent to all-trans-retinal. However, this can also result in a new state that is not formed with the full agonist. Therefore, rhodopsin studies suggest that that partial agonism may result in either a reduced number of fully active receptors or conformations which are not capable of fully engaging the signal transduction process. Structures of other GPCRs in complex with partial agonists are required to determine their effects on conformation.An example makes the hideous complexity clear. The mu-opioid receptor is activated by several ligands including morphine, etorphine and fentanyl. However, morphine acts only as a partial agonist in effecting a phosphorylation endpoint whereas the other two act as full agonists. But it gets more interesting. While morphine effects phosphorylation of the kinase ERK through activation of PKC (protein kinase C), etorphine also activates ERK but by activation of beta-arrestin. Thus the same endpoint can be effected through different pathways. And it doesn't even stop there. Morphine causes the phosphorylated ERK to stay in the cytoplasm while etorphine causes the ERK to translocate to the nucleus. Not done yet; in addition, morphine can reverse its role and act as a full agonist on the adenylyl cyclase pathway.
Categories: Uncategorized
February 5th, 2010
So last night, I had the privilege(?) of driving to Chicago to watch a taping of NPR's "Irreverent News Quiz" Wait Wait... Don't Tell Me!. For those of you who are unfamiliar with the show, each week they record an hour long news-quiz-comedy show either at the Chase Theater in downtown Chicago or at various locations throughout the USA (for example, they're heading out to New Orleans, LA in March). It's a great show, filled with improvised humor and actual information about the good (and not-so-good) news being produced each week.
Categories: Uncategorized
February 5th, 2010
I hate to do another post on this subject, after a good part of the week has been devoted to layoff news and the like, but this one is too much to ignore. A reader sent along this link, which quotes a Morgan Stanley appraisal of the pharma industry as an investment. Here's what they're telling their clients:
". . .Still significant value in Pharma - we see material upside to ROIC [return on invested capital], earnings and multiples as Pharma withdraws from most internal small-molecule research and reallocates capital to in-licensing and other non-pharma assets. Worsening generic pressure and R&D management changes lead us to expect material cuts to internal small research spend (~40% total R&D) in 2010/11, after a decade of dismal internal R&D returns. We expect AstraZeneca and Sanofi-Aventis to be among the leaders in externalizing research, and this is a key driver of our upgrade of AstraZeneca today to Overweight.
Reinvestment of internal research savings into in-licensing will yield three times the likely return, we calculate. Under in-licensing deals, downside risk for pharma companies is currently materially lower than for internally developed drugs. Although upside is also capped by pay-aways and milestone obligations, the net present value of these payments is more than offset by the lower risk-adjusted invested capital. Over one-third of pharma R&D spend is in pre-phase II, where the probability of reaching the market is <10%. our proprietary analysis indicates that, unless the probability of an in-house molecule reaching the market is 30% or more, the risk-adjusted economic value added, or eva, is three times higher under the external research model, with a greater predictability."
It could be said in fewer words, but it's all there. If you're looking for the reason the big companies are doing what they're doing, look no further. Agree with it or not, there's a case to be made - and there's Morgan Stanley, making it - that the cost of running new drug projects in big pharma is just too high relative to the risks of failure. Those returns, in fact, are calculated to be off by a factor of three.
You may not believe that factor, and I have to say, I found it hard to believe myself. But let's say the Morgan Stanley folks have their numbers off. Perhaps it's only twice as profitable to bring in outside drugs as it is to develop them internally. Don't believe that one, either? Maybe it's only 25% more profitable - can you imagine making a move that would increase your company's return on investment by 25%? Industries get remade by such changes at the margin, and this one is remaking ours. Why do we have any internal R&D left at all, if those figures are anywhere near right?
Well, no one's tried to run a large company entirely by in-licensing, and I think that there are a lot of reasons why that wouldn't work. (For one thing, I don't think that there are enough things to in-license, and if one or more large companies announced that they were doing that exclusively, the price of each deal would go right up). And there needs to be some internal expertise left, if only to evaluate those external drug candidates to make sure you're not being taken. But still. All this means is that internal R&D will stay around, but it has to get cheaper and will very likely get smaller.
We can argue about the assumptions behind all this, but there's no doubt that a compelling business case can be made for this world view. Anyone who wants to argue differently - and a lot of us do - will have to come up with solid numbers and reasoning for why it just ain't so. I'm not sure such numbers exist.
There are many corollaries to this line of thought. One of them - and I hate to bring this up, considering all the horrible layoff news recently - is that one of the most psychologically comforting theories that we in R&D have for our present fix is likely wrong. I refer to the "Evil Clueless MBA CEO" theory, which has its satisfactions, but is a hazardous way to think. It is always dangerous to assume that people who do things you disagree with are doing them because they're just idiots or because they're innately malicious. In general, I'd say that the first explanation to jettison is malice, followed by stupidity (Hanlon's Razor). What that leaves you with is that these actions, stupid and malicious though they may appear, are probably being done for reasons that appear valid to the people doing them. I know, I know - some of these reasons are things like "So I can keep my high-paying CEO job", and we can't ignore that one. But a good way to lose a high-paying CEO job is to try to tell your board of directors (and your shareholders) why you're going to pass up an opportunity to get three times your ROIC.
Another thing to think about is, if these cost estimates are right, how did we get here? The best reason I can think of for such a disparity is that small companies (the source of these in-licensed drugs and projects) are often betting their entire existence on these ideas. They are very strongly motivated to do whatever they can do to get them to work (sometimes a bit too motivated, but that risk is already factored in), and if things don't pan out, they usually disappear. Basically, the in-licensing world unloads the risk from the large pharma company (and its shareholders) onto the investors in the smaller ones. The cost disparity will exist for as long as people are willing to back smaller companies. Now, this isn't to say that the big companies are always going to do a great job picking what to bring in. We've been talking a lot, for example, about the GSK-Sirtris deal, and that one may or may not work out. But the idea of doing big in-licensing deals in general - that's a different story, no matter how any individual company manages to execute it.
What that also means is that more of us are going to end up working for those smaller companies (which is something that I, and several commenters around here, have been saying for a while). If the large pharma outfits are going to devote more money to in-licensing, there will then be more opportunities for people developing things for them to in-license. The rough part is that all these structural changes in the drug industry are taking place (largely by coincidence, I think) during economic conditions which make funding such companies difficult.
And then there's the internal cost-cutting, for the R&D that's actually staying at the big companies. That, of course, generally means sending a lot of it to China, or wherever else it can be done more cheaply. And that's going to continue as long as it can indeed be done more cheaply, which means "not forever". Costs are already rising in China and India, although they have a good ways to go before they catch up to the US and Europe. I know that we can argue about how well that whole idea is going to work - there are clearly inefficiencies to doing a lot of your work through outsourcing, but as long as those don't eat up all the cost savings, it's still going to keep happening.
This, as a side note, is why I think that one of the suggestions that gets floated here in the comments from time to time, the idea of forming a "medicinal chemist's union", is completely useless. Unions form when workers have the leverage to preserve a higher-cost business model. In the end, the big industrial concerns of the early 20th century had to have workers, and they had to have them in certain locations, so the unions always had the threat of going on strike. At attempt to lower the boom under these conditions would result in everything going to China, and damned quickly.
So. . .what's happening to us, and to our industry, is not really mysterious. Our cost structure does not look to be supportable, and since there are cheaper alternatives that appear to be feasible, those will get tried. The disruption and destruction that all this is causing is real, of course. But the best I can offer is to try to understand what's driving all this upheaval, because that might help people to figure out how to protect their own jobs or where to jump next. Everyone has to give this some serious thought, because I don't see any reason why all this won't keep going on for some time to come.
Categories: Uncategorized
February 5th, 2010
Categories: Chemistry
http://nucleus.chemistryblog.net /
