HPC and structure-based drug design
May 5, 2008
Here is the abstract of a paper in Hypertension entitled Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents.
Angiotensin-converting enzyme 2 (ACE2) is a key renin-angiotensin system enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system, and its overexpression by gene transfer is beneficial in cardiovascular disease. Therefore, our objectives were 2-fold: to identify compounds that enhance ACE2 activity using a novel conformation-based rational drug discovery strategy and to evaluate whether such compounds reverse hypertension-induced pathophysiologies. We used a unique virtual screening approach. In vitro assays revealed 2 compounds (a xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity in a dose-dependent manner. Acute in vivo administration of the xanthenone resulted in a dose-dependent transient and robust decrease in blood pressure (at 10 mg/kg, spontaneously hypertensive rats decreased 71+/-9 mm Hg and Wistar-Kyoto rats decreased 21+/-8 mm Hg; P<0.05). Chronic infusion of the xanthenone (120 microg/day) resulted in a modest decrease in the spontaneously hypertensive rat blood pressure (17 mm Hg; 2-way ANOVA; P<0.05), whereas it had no effect in Wistar-Kyoto rats. Strikingly, the decrease in blood pressure was also associated with improvements in cardiac function and reversal of myocardial, perivascular, and renal fibrosis in the spontaneously hypertensive rats. We conclude that structure-based screening can help identify compounds that activate ACE2, decrease blood pressure, and reverse tissue remodeling. Administration of ACE2 activators may be a valid strategy for antihypertensive therapy.
Here’s the HPCwire story, which really doesn’t tell me much other than really high throughput docking, but they use words like
That in itself is a significant accomplishment because no one has ever specifically identified a compound that enhances the activity of an enzyme using a rational structure-based approach
Anyone have a subscription to Hypertension? I am really curious cause nothing I read screams “unique” to me. Of course, I can just wait till tomorrow and try and get to the paper from work.
Update: Got the paper, and still don’t get the fuss. It’s an elegant virtual screening strategy, but I wouldn’t say it’s revolutionary. I was hoping to see something more advanced, e.g. protein flexibility, better energy functions, etc.
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Technorati Tags: Virtual Screening, Structure-based Drug Design, Hypertension, High Performance Computing
Bio-IT World day 2 - iPhones, Virtualization, EC2 and the Semantic Web
April 30, 2008
A quick report on Day 2 of Bio-IT World.
The day started with a keynote by Josh Boger, founder and CEO of Vertex. His talk spanned several real world examples and some food for thought. Highlights
- Vertex has made active use of a MedChem ELN, which has been extended to their entire MedChem community, including external partners. In his own words the goal was “enabling the virtual research organization”
- Metric of success was user adoption and there were some good analytics supporting uptake
- He spoke at length about the HCV program, where they have used extensive predictive modeling and simulation
- Clinical data has backed up their predictive modeling (they’re in Phase III now)
- They have avoided some experiments (carried out by competitors in one case) that their models suggested they avoid
- He ended by talking a lot about communication and how technology can impact the healthcare system. Much of this section of his talk was around the iPhone. For example how the iPhone can be used to track RFID tagged pill bottles, patient exercise regimens, carry patient records, monitor weight, etc. They’re actually implementing some of these ideas
There were many other talks to attend, and I won’t bore you with some of the details, but I will talk about one talk, a talk by Chris Dagdigian of The BioTeam, a small boutique consulting shop, which readers of this blog will know via mentions of Michael Cariaso. Chris spent a lot his talk discussing the economics of storage and the kinds of storage, etc available these days and trends in storage and computing. Perhaps it shows how much of a geek I am, but this was a dream talk, one full of hardware specs, pictures of data centers, etc. It is clear that virtualization is big; Chris’ preference being Xen. There was a cool slide on meta-virtualization (a virtual machine inside a virtual machine inside a virtual machine). Two thoughts really resonated with me; first was his distaste for classical Grid Computing, which I have long considered impractical for most companies. The second was his strong support for Amazon Web Services, especially EC2. Apparently, every single BioTeam consultant has independently deployed an EC2 solution, i.e. they’ve all come to the same conclusion. Can’t wait to see this talk next year to find out where they’ve gone with AWS. One thing he said which also resonated was to talk about the death of the small cluster. Today and in the future, we will either have multicore (8-16 cores) on our desktops or dial up cloud resources. His slides will be available somewhere. Can’t wait to get my hands on them. This was a GREAT talk.
One of the highlights for me was attending the W3C Semantic Web HCLSIG lunch. I got to meet people I know (Eric Neumann), people I have interacted with online (Vipul Kashyap) and followed (John Wilbanks from Science Commons). And I got to say hello to Sir Tim Berners-Lee, who needs no introduction.
Another highlight for me. I got to finally meet Joe Landman, whose JackRabbit got a good plug in the BioTeam talk as well. It was great to meet Joe with whom I’ve been having a conversation via our respective blogs for quite a while now.
Met several former colleagues and customers as well. Bio-IT World has definitely been one of the better conferences I have had a chance to attend in terms of interest and people.
Image via Wikipedia
Technorati Tags: Bio-IT World, W3C, BioTeam, BioIT
Wallstrip and the life sciences part II
April 3, 2008
Previously I had pointed to Lindsay Campbell’s over the top coverage of Illumina. Lindsay has since moved on to another CBS show, but Wallstrip lives on. Today, Julie Alexandria covered Phase Forward. I know she’s trying to be funny and all that, but sometimes I cringe when the mainstream press covers anything health and pharma related. This coverage does nothing to change my mind. Judge for yourself.
Technorati Tags: Phase Forward, Wallstrip
Data-driven trial feasibility
April 1, 2008
Algorithms or data? I can see the arguments starting right now. Just kidding of course, but a company called Provisio has a service called iTrials that captures information from 60 million patients to help make decisions about patient enrollment. The key goal is to try and figure out how many patients can be enrolled in a trial, and being able to make good decisions there can save a lot of money.
Two thoughts came to mind
- First of all how much data is good data. 60 million sounds like a lot, but in the grand scheme of things, with trials going global it may not really be that much
- When patient enrichment and other trial approaches, driven by genetics, become more common, how is this information going to be used?
I am early in my days of understanding trial selection, etc, so there are always a lot of questions. Good food for thought anyway.
Technorati Tags: Clinical Trials
Peer-review and openness
March 15, 2008
This is an interesting battle. Big Pharma vs. traditional peer-reviewed publishing.
A judge ruled that peer-reviewed documents requested by Pfizer could not be released by the New England Journal of Medicine (NEJM). Personally I believe peer-review should not be closed, although I am on the fence about the anonymity of reviewers.
Technorati Tags: Pfizer, NEJM, Peer Review
