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Screening probes and probing screens
March 9th, 2010, No Comments
High Throughput Screening (HTS), with all its strengths and limitations, is still the single-best way to discover novel interesting molecules in drug discovery. Thomas Kodadek of Scripps Florida has an interesting article on screening in the latest issue of Nat. Chem. Biol which is a special issue on chemical probes.
Kodadek talks about the very different properties required for drugs and probes and the limitations and unmet needs in current HTS strategies. He focuses on mainly two kinds of screening; functional assays and binding assays. The former can consist of phenotypic screening wherein one is only interested in a particular cellular response. This is more useful for drugs. However for probes, target selectivity is important and one must have knowledge of the target. HTS hits can hit all kinds of protein targets, thus making it hard to find out if your compounds are being selective. Mutagenesis and siRNA studies can shed light on target selectivity but this is not easy to do.
One of the possible solutions Kodadek suggests to circumvent the problem of gauging selectivity is to use binding assays instead of functional assays. He notes a pretty clever idea used in binding assays; that of throwing in cell extracts with miscellaneous proteins that could mop up greasy, non-selective compounds. This strategy cannot be easily used in functional assays. Binding assays are also typically less expensive than functional assays.
There is also a discussion of some of the very practical problems associated with screening. Screening typically has low hit rates and more importantly, hits from screening are not leads. You usually need a dedicated team of synthetic chemists to make systematic SAR modifications to these hits to optimize them further. As the author says, few synthetic chemists wish to serve as SAR facilities for their biologist colleagues. Plus it is not easy to lure industrial chemists to serve this function in academia (although the present economic climate may have made this easier). Thus, biologists with no synthetic background need to be able to make at least some modifications to their hits. For this purpose Kodadek suggests the use of modular molecules with easily available building blocks which can be cheaply and easily connected together by relatively inexperienced chemists; foremost in his recommendations are peptoids, N-substituted oligoglycines which are biologically active and easy to synthesize. Thus, if libraries for screening are enriched in such kinds of molecules, it could make it easy for biologists without access to sophisticated synthetic chemists and facilities to cobble together leads. Of course this would lead to a loss of diversity in the libraries, but that’s the tradeoff necessary for going down the long road from hit to lead.
Lastly, Kodadek briefly talks about prospects for screening in academia. Academic drugs discovery is graduually becoming more attractive with the recent long lull in industry. However academic scientists are typically not very familir with the post-synthesis optimization of drugs including optimization of metabolic properties, bioavailability and PK. Academic scientists who can pursue such studies or partner with DMPK contracting companies may be paid back their dues.
One topic which Kodadek does not mention is virtual screening (VS). VS can complement HTS and at least some studies indicate that the rate of success in VS can match, if not exceed, that in HTS. In addition, new ligand-based methods which use properties such as molecular shape to screen for compounds similar to given hits can also valuably complement HTS follow up studies.
Screening is still the best bet for discovering new drugs, but hit rates are typically still very low (1% would be a godsend). Only a concerted effort at designing libraries, ensuring selectivity and synthetic accessibility will make it easier.
Kodadek, T. (2010). Rethinking screening Nature Chemical Biology, 6 (3), 162-165 DOI: 10.1038/nchembio.303
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Running Shoe Conundrum
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I need a new pair of shoes.I am unconvinced that getting the same type of shoe will be the best option, especially because the last time I did my injury flared up. I also have done a fair amount of reading/listening to experts and non-experts reg…
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A GSK/Sirtris Wrap-Up
March 9th, 2010, No Comments
Nature Biotechnology weighs in on the GSK/Sirtris controversy. They have a lot of good information, and I’m not just saying that because someone there has clearly read over the comments that have showed up to my posts on the subject. The short form:
The controversy over Sirtris drugs reached a tipping point in January with a publication by Pfizer researchers led by Kay Ahn showing that resveratrol activates SIRT1 only when linked to a fluorophore. Although Ahn declined to be interviewed by Nature Biotechnology, a statement issued by Pfizer says the group’s findings “call into question the mechanism of action of resveratrol and other reported activators of the SIRT1 enzyme.”
Most experts, however, say it’s too soon to write off Sirtris’ compounds altogether, assuming they’re clinically useful by mechanisms that don’t involve sirtuin binding. And for its part, GSK won’t concede that Sirtris’ small molecules don’t bind the targets. In an e-mailed statement, Ad Rawcliffe, head of GSK’s WorldWide Business Development group, says, “There is nothing that has happened to date, including the publication [by Pfizer,] that suggests otherwise.”
We’ll see if GSK and Sirtris have some more publications ready to silence their detractors. But what will really do that, and what we’ll all have to wait for, are clinical results.
Hope Darn Well Springs Eternal
March 9th, 2010, No Comments
Well, it takes all kinds to make a market. And the collapse in Medivation’s shares after their disastrous Phase III results the other day seem to have brought out some hopeful buyers. Take this guy:
. . .I’m telling you right now, I believe that sell-off has gone twice as deep as good sense can justify. At least, that’s the way I see it.
First off, we should understand that drug trials are Medivation’s business. Clinical trials are what the company does. This failed phase 3 study isn’t to be considered a crash into a brick wall. It’s not a crippling lawsuit. It’s not the loss of a major customer account. It’s simply a sudden downshift, a temporary change of gears. In many ways, for Medivation, it’s just one facet of business as usual.
As I look at Medivation’s one-year and three-year performance charts, the opening to invest is just screaming at me. . .
All I can say is “Go for it, chief!” I might just add, very quietly, that early-stage drug discovery is not really the kind of business where one-year and three-year stock performance is much of a guide. And it’s also worth remembering that although clinical trials are indeed what drug companies do, we try not to do big honking Phase III face-plants. You don’t start clinical trials that you think are going to end that way, so a crash into a brick wall is actually not a bad analogy.
But hey – the dented hubcaps have just about finished wobbling around into the dust, and who knows, the stock might actually bounce back up a little bit, thanks to the brave and the foolhardy. But if Medivation is ever to make it back to where it was, I don’t see how it’s going to be because of Dimebon.
Via RJAlvarez on Twitter, who says “Tough call, but this is perhaps the worst post recommending a biotch stock I’ve ever read.”
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Bad News at Exelixis
March 8th, 2010, No Comments
I’m hearing from more than one source that Exelixis has laid off about 40% of their work force, which is somewhere around 250 people (the numbers I get don’t all agree). This seems to be across the board, all departments, and most everyone is being asked to leave today.
The Bay area biotech scene doesn’t seem to be at its healthiest these days (although it’s still in better shape than San Diego, from the sound of it), but this isn’t going to help it one bit. . .
(Oligomer) size does matter
March 8th, 2010, No Comments
I swear to god, they’re just doing this on purpose now:
“Synthesis and molecular properties of donor–π-spacer–acceptor ynamides with up to four conjugated alkyne units.” pi-spacers. Because they space out pi orbitals. Girl.
However, the results of the paper did show that “intermolecular charge transfer” does “decrease” as the “length of the pi-spacer” “increases” beyond two [...]
