MedWorm provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest medical blog items that have been tagged with 'assays'. Sat, 03 Sep 2011 02:38:08 +0100 http://www.medworm.com/index.php?rid=5140274&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2011%2F08%2F18%2Fis_anyone_doing_the_pfizer_screening_deal.php A couple of years ago, I wrote here about an initiative from Pfizer. They were proposing letting other (smaller) companies screen their compound collection, with rights to be worked out if something interesting turned up. The thing is, I haven't heard about anyone taking them up on it. Does anyone know if this ever got off the ground, or did it get lost in the trackless Pfizer territories somewhere? It sounded like a reasonable idea in some ways, and I'm curious if it ever went anywhere. . . (Source: In the Pipeline) In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=5140274 Thu, 18 Aug 2011 15:14:11 +0100 5140274 http://www.medworm.com/index.php?rid=4795046&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2011%2F05%2F06%2Fin_which_i_do_not_lose_it_for_once.php PNAS recently came out with a special concentration of chemistry papers, and they're worth a look. The theme is the synthesis of chemical probes, which makes me think that maybe Stuart Schrieber can guest-edit an issue of Vogue next. Today I'm going to highlight one from the Broad Institute on diversity-oriented synthesis (DOS), and next week I'll get to some more. OK, that was something of a come-on for regular readers of this site, who now will be listening for the sound of grinding wheels coming up to speed, the better to sharpen the Sword of Justice. I've said unfriendly things in the past about DOS and some of the claims made for it. The point of much of this work has been lost on me, and I'm a pretty broad-minded guy. (That word, in this case, rhymes with "sawed", not with "load"). ... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=4795046 Fri, 06 May 2011 11:58:29 +0100 4795046 http://www.medworm.com/index.php?rid=4780477&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2011%2F05%2F03%2Fa_look_inside_the_compound_collections.php Now here's a comparison that you don't get to see very often: how much do two large pharma compound collections overlap? There's a paper going into just that question in the wake of the 2006-2007 merger between Bayer and Schering AG. (By two coincidences, this paper is in the same feed as the one that I highlighted yesterday, and that merger is the one that closed my former research site out from under me). Pre-merger, Bayer had over two million structures in its corporate collection, and Schering AG had just under 900,000. Both companies had undertaken recent library clean-up programs, clearing out undesirable compounds and adding both purchased and in-house diversity structures. Interestingly, it turns out that just under 50,000 structures were duplicated across both collections, about ... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=4780477 Tue, 03 May 2011 13:23:25 +0100 4780477 http://www.medworm.com/index.php?rid=4446013&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2011%2F02%2F07%2Ffragments_versus_dos_a_showdown.php Nature has side-by-side editorial pieces about fragment-based drug discovery versus diversity-oriented synthesis (DOS). I've written about both topics here before (DOS here and here, fragments here and here), and it should be fairly clear that I favor the former. But both ideas deserve a hearing. Background, for those who aren't having to think about this stuff: the fragment-based approach is to screen a reasonable set (hundreds to low thousands) of small (MW 150 to 300) molecules. You won't find any nanomolar hits that way, but you will find things that (for that molecular weight) are binding extremely efficiently. If you can get a structure (X-ray, most of the time), you can then use that piece as a starting point and build out, trying to keep the binding efficiency high as you go. Dive... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=4446013 Mon, 07 Feb 2011 14:16:46 +0100 4446013 http://www.medworm.com/index.php?rid=4065598&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2010%2F10%2F13%2Fa_cautionary_tale.php For those who haven't seen it, I heard Adam Renslo of UCSF present this work yesterday. His group was looking for inhibitors of cruzain, a target for Chagas' disease, which is certainly a worthy cause (and a tough target). They found a series of oxadiazoles, which are, to be sure, rather ugly (but no uglier than a lot of chemical matter you see in the kinase field, among others). They had affinity, they had reasonable SAR, and the team drove the potencies down against the target. . .only to find, late in the game, that it was all an illusion. These compounds are aggregators. (That link takes you to a post about a follow-up paper from the UCSF folks, covering this debacle and others). What's striking is that this artifact (compound aggregation under the assay conditions) mimicked a plausib... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=4065598 Wed, 13 Oct 2010 11:57:24 +0100 4065598 http://www.medworm.com/index.php?rid=3746974&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2010%2F07%2F12%2Fnatural_products_not_the_best_fit_for_drugs.php Stuart Schreiber and Paul Clemons of the Broad Institute have a provocative paper out in JACS on natural products and their use in drug discovery. As many know, a good part of the current pharmacopeia is derived from natural product lead structures, and in many other cases a natural product was essential for identifying a target or pathway for a completely synthetic compound. But are there as many of these cases as we think - or as there should be? This latest paper takes a large set of interaction data and tries to map natural product activities on to it. It's already know that there are genes all up and down the "interactome" spectrum, as you'd expect, with some that seem to be at the crossroads of dozens (or hundreds) of pathways, and others that are way out on the edges. And it's been... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=3746974 Mon, 12 Jul 2010 12:11:41 +0100 3746974 http://www.medworm.com/index.php?rid=3416314&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2010%2F03%2F29%2Fcompounds_and_proteins.php For the medicinal chemists in the audience, I wanted to strongly recommend a new paper from a group at Roche. It's a tour through the various sorts of interactions between proteins and ligands, with copious examples, and it's a very sensible look at the subject. It covers a number of topics that have been discussed here (and throughout the literature in recent years), and looks to be an excellent one-stop reference. In fact, read the right way, it's a testament to how tricky medicinal chemistry is. Some of the topics are hydrogen bonds (and why they can be excellent keys to binding or, alternatively, of no use whatsoever), water molecules bound to proteins (and why disturbing them can account for large amounts of binding energy, or, alternatively, kill your compound's chances of ever bind... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=3416314 Mon, 29 Mar 2010 13:17:20 +0100 3416314 http://www.medworm.com/index.php?rid=3399165&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2010%2F03%2F24%2Fdrugs_and_their_starting_points.php I've spoken about fragment-based drug design and ligand efficiency here a few times. There's a new paper in J. Med. Chem. that puts some numbers on that latter concept. (Full disclosure - I've worked with its author, although I had nothing to do with this particular paper). For the non-chemists in the crowd who want to know what I'm talking about, fragment-based methods are an attempt to start with smaller, weaker-binding chemical structures than we usually work with. But if you look at how much affinity you're getting for the size of the molecules, you find that some of these seemingly weaker compounds are actually doing a great job for their size. Starting from these and building out, with an eye along the way toward keeping that efficiency up, could be a way of making better final comp... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=3399165 Wed, 24 Mar 2010 12:05:57 +0100 3399165 http://www.medworm.com/index.php?rid=3318647&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2010%2F03%2F01%2Fcalorimetry_what_say_you.php I've been involved in a mailing list discussion that I wanted to open up to a wider audience in drug discovery, so here goes. We spend our time (well, a lot of it, when we're not filling out forms) trying to get compound to bind well to our targets. And that binding is, of course, all about energy: the lower the overall energy of the system when your compound binds, relative to the starting state, the tighter the binding. That energy change can be broken down (all can all chemical free energy changes) into an enthalpic part and an entropic part (that latter one depends on temperature, but we'll assume that everything's being done at a constant T and ignore that part). Roughly speaking, the enthalpic component is where you see effects of hydrogen bonds, pi-pi stacking, and other such "prod... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=3318647 Mon, 01 Mar 2010 14:07:36 +0100 3318647 http://www.medworm.com/index.php?rid=3208676&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2010%2F01%2F26%2Fthe_infinitely_active_impurity.php Yesterday's post touched on something that all experienced drug discovery people have been through: the compound that works - until a new batch is made. Then it doesn't work so well. What to do? You have a fork in the road here: one route is labeled "Blame the Assay" and the other one is "Blame the Compound". Neither can be ruled out at first, but the second alternative is easier to check out, thanks to modern analytical chemistry. A clean (or at least identical) LC/MS, a good NMR, even (gasp!) elemental analysis - all these can reassure you that the compound itself hasn't changed. But sometimes it has. In my experience, the biggest mistake is to not fully characterize the original batch, particularly if it's a purchased compound, or if it comes from the dusty recesses of the archive. Yo... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=3208676 Tue, 26 Jan 2010 13:29:04 +0100 3208676 http://www.medworm.com/index.php?rid=2992838&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2009%2F11%2F13%2Flumpy_assay_results.php When we screen zillions of compounds from our files against a new drug target, what can we expect? How many hits will we get, and what percentage of those are actually worth looking at in more detail? These are long-running questions, but over the last twenty years some lessons have been learned. A new paper in J. Med. Chem. emphasizes one of the biggest ones: if at all possible, run your assays with some sort of detergent in them. Why would you do a thing like that? Compound aggregation. The last few years have seen a rapidly growing appreciation of this problem. Many small molecules will, under some conditions, clump together in solution and make a new species that has little or nothing to do with their individual members. These new aggregates can bind to protein surfaces, mess up fluo... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=2992838 Fri, 13 Nov 2009 13:53:13 +0100 2992838 http://www.medworm.com/index.php?rid=2800663&cid=t_128471_136_f&fid=37846&url=http%3A%2F%2Fhealthinfoispower.wordpress.com%2F2009%2F09%2F15%2Ffda-clears-vermillions-ova1-test-to-determine-likelihood-of-ovarian-cancer-in-women-with-pelvic-mass%2F The U.S. Food and Drug Administration cleared a test that can help detect ovarian cancer in a pelvic mass that is already known to require surgery. The test, called OVA1, helps patients and health care professionals decide what type of surgery should be done and by whom. First Lab Test That Can Indicate Ovarian Cancer Prior [...] (Source: Libby's H*O*P*E*) Libby's H*O*P*E* blogs http://www.medworm.com/rss/comments.php?id=2800663 Wed, 16 Sep 2009 04:45:59 +0100 2800663 http://www.medworm.com/index.php?rid=2553225&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2009%2F06%2F29%2Feli_lilly_gives_it_away.php Not long ago, I wrote about a Pfizer program for smaller companies to come screen their targets against Pfizer's compound bank. Now Eli Lilly has flipped that around. In an initiative to bring other people's compounds out of the stockrooms and off the shelves, they'll screen them for free. These aren't single-target assays. The company has four phenotypic screens going (for Alzheimer's, diabetes, cancer, and osteoporosis) and will look for improvement by any mechanism that comes to hand. No chemical structure information is shown to Lilly (I assume that they just know the molecular weight so they can run a dilution series). If something looks interesting, the company and the owners of the chemical matter have 120 days to come to terms for any further development deal - if not, then all ri... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=2553225 Mon, 29 Jun 2009 12:33:26 +0100 2553225 http://www.medworm.com/index.php?rid=2424493&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2009%2F05%2F19%2Fwant_to_screen_pfizers_compounds_sign_here.php I've heard that Pfizer is doing something unusual with its proprietary compound collection: they're offering to let other people screen it. Now, that's quite a step. Most companies guard their compounds pretty closely, considering them to be key assets. But I'm told that Pfizer has been meeting with several other (mostly smaller) companies, offering their (entire?) compound library as a screening resource. As I understand it, you need to come to them with a reasonably formatted HTS assay, and there's a fee in the high hundreds of thousands to run the screen. That doesn't seem like much of a moneymaker, to be honest. The whole thing appears to me to be a way for Pfizer to strike deals with a number of other companies, since the compounds that come out of the screen will (likely as not) b... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=2424493 Tue, 19 May 2009 15:43:26 +0100 2424493 http://www.medworm.com/index.php?rid=2241392&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2009%2F03%2F06%2Ftie_me_molecule_down_sport.php There are a huge number of techniques in the protein world that relay on tying down some binding partner onto some kind of solid support. When you’re talking about immobilizing proteins, that’s one thing – they’re large beasts, and presumably there’s some tether that can be bonded to them to string off to a solid bead or chip. It’s certainly not always easy, but generally can be done, often after some experimentation with the length of the linker, its composition, and the chemistry used to attach it. But there are also plenty of ideas out there that call for doing the same sort of thing to small molecules. The first thing that comes to mind is affinity chromatography – take some small molecule that you know binds to a given protein or class of proteins well, attach it to som... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=2241392 Fri, 06 Mar 2009 13:19:07 +0100 2241392 http://www.medworm.com/index.php?rid=2121984&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2009%2F01%2F21%2Fthe_hideous_numbers_of_compounds.php I was blithely throwing around the term “chemical space” in yesterday’s post. So, what am I talking about, and how much room is in there, anyway? Let's narrow it down to organic compounds, to start with, or at least compounds that are mostly organic. A working definition, as far as people interested in biology and medicine go, might then be “the domain of chemical compounds compatible with living systems”. That excludes the red-hot reactive stuff and the unstable exploders, but leaves most everything else. Let’s also ignore macromolecules of various kinds and cut back to “drug-like” sizes – say, molecular weight 500 or less. That way we don’t have infinite numbers of polymers going off in all directions; that should help. And that leaves us with. . .? A ridiculously l... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=2121984 Wed, 21 Jan 2009 13:25:10 +0100 2121984 http://www.medworm.com/index.php?rid=1170211&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2008%2F01%2F22%2Fthese_fragments_i_have_shored_against_my_ruins.php There’s been a big trend the last few years in the industry to try to build our molecules up from much smaller pieces than usual. “Fragment-based” drug discovery is the subject of many conferences and review articles these days, and I’d guess that most decent-sized companies have some sort of fragment effort going on. (Recent reviews on the topic, for those who want them). Many different approaches come under that heading, though. Generally, the theme is to screen a collection of small molecules, half the size or less of what you’d consider a reasonable molecular weight for a final compound, and look for something that binds. At those sizes, you’re not going to find the high affinities that you usually look for, though. We usually want our clinical candidates to be down in the... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=1170211 Tue, 22 Jan 2008 14:23:08 +0100 1170211 http://www.medworm.com/index.php?rid=728631&cid=t_128471_149_f&fid=35776&url=http%3A%2F%2Fpipeline.corante.com%2Farchives%2F2007%2F07%2F10%2Ftravels_in_numerica_deserta.php There's a problem in the drug industry that people have recognized for some years, but we're not that much closer to dealing with it than we were then. We keep coming up with these technologies and techniques which seem as if they might be able to help us with some of our nastiest problems - I'm talking about genomics in all its guises, and metabolic profiling, and naturally the various high-throughput screening platforms, and others. But whether these are helping or not (and opinions sure do vary), one thing that they all have in common is that they generate enormous heaps of data. We're not the only field to wish that the speed of collating and understanding all these results would start to catch up with the speed with which they're being generated. But some days I feel as if the two cu... In the Pipeline blogs http://www.medworm.com/rss/comments.php?id=728631 Tue, 10 Jul 2007 23:09:56 +0100 728631 http://www.medworm.com/index.php?rid=706581&cid=t_128471_113_f&fid=34933&url=http%3A%2F%2Fpalmdoc.net%2F%3Fp%3D1305 Spotted Pulmonary Embolism Paths v1.0 in freewarepalm.com Description: Pulmonary Embolism Paths is a FREE program that outlines the risk factors, signs & symptoms and criteria for low/intermediate/high clinical suspicion for Pulmonary Embolism. Finally, it provides algorithms for how to arrive at your final diagnosis based upon D-dimer assays, V/Q Scans and Pulmonary Angiography. (Source: The Palmdoc Chronicles) The Palmdoc Chronicles blogs http://www.medworm.com/rss/comments.php?id=706581 Sat, 30 Jun 2007 04:00:00 +0100 706581 http://www.medworm.com/index.php?rid=525719&cid=t_128471_107_f&fid=35025&url=http%3A%2F%2Frrresearch.blogspot.com%2F2007%2F04%2Fpreparing-for-e-coli-sxy-induction.html The strain and plasmids we've been waiting for arrived on Wednesday (thank you to the Pugsley lab), so now I can get started on my attempts to induce sxy expression in E. coli. And we do already have an E. coli sxy knockout from the Japanese group, so solving the recombineering problems isn't critical (though I should get to work on that anyway).What to do first? The initial tests will use a reporter strain carrying a fusion of the ppdD gene to lacZ. The person who sent the strain says it should be pale blue on X-gal plates, indicating weak baseline expression of lacZ. I should first characterize its lacZ expression more precisely by growing it under defined conditions and measuring the amount of beta-galactosidase (the lacZ product) with the substrate ONPG. This is a simple classic assay,... RRResearch blogs http://www.medworm.com/rss/comments.php?id=525719 Fri, 06 Apr 2007 12:42:00 +0100 525719