• We all know just how useless HTS is, don't we?


    Well, there's a great paper in a recent Nature Reviews Drug Discovery from a cross-industry set of authors on a retrospective analysis of HTS in drug discovery - lots of data, lots of examples, and a balanced argument for the case for high-throughput screening in modern pharmaceutical discovery.

    %T Impact of high-throughput screening in biomedical research
%J Nature Rev. Drug Disc.
%V 10
%D 2012 
%P 188-195
%A R. Macarron
%A M.N. Banks
%A D. Bojanic
%A D.J. Burns
%A D.A. Cirovic
%A T. Garyantes
%A D.V.S. Green
%A R.P. Hertzberg
%A W.P. Janzen
%A J.W. Paslay
%A U. Schopfer
%A G.S. Sittampalam

  • New Drug Approvals 2012 - Pt. VIII - Peginesatide (OmontysTM)






    ATC code: B03XA (incomplete)

    On March 27, the FDA approved Peginesatide for the treatment of anemia due to chronic kindney disease (CDK) in patients on dialysis. CDK is a slow but progressive loss of kidney function that can be caused by diabetes mellitus,  hypertension and glomerulonephritis, among others. One of the symptoms in the advanced stages of CDK is anemia, a decrease in the number of red blood cells and hence the hemoglobin (adult hemoglobin: heterotetramer of two copies of P69905 and two copies of P68871) content of the blood. Anemia in patients suffering from CDK is caused by reduced production of erythropoetin, a hormone that regulates the levels of red blood cells and is synthesized predominantly in the cortex of the kidney.

    Anemia induced by CDK can be treated by supplying exogenous erythroepotin or analogs of this hormone (e.g. Methoxy polyethylene glycol-epoetin beta, CHEMBL1201829). The collective term for these substances is erythropoiesis-stimulating agent (ESAs). Like endogenous erythropoetin, ESAs exert their effect through binding of the erythropeotin receptor (EpoR, Uniprot P19235) and subsequent activation of the JAK2 (Uniprot O60674) STAT5A (Uniprot P42229) pathway, which results in increased survival of erythrocyte progenitors.

    Peginesatide is an ESA with no sequence homology to erythropoetin. Instead, it is composed of two synthetic 21 amino-acid peptides that are linked through a lysine branched PEG chain, as shown below.


    The dimeric peptide has a molecular weight of about 4.9 kDa, and the PEG chain has a molecular weight of approximately 40kDa. Peginasetide is dosed as an acetate salt. The empirical formula of the free base is C2031H3950N62O958S6 and total molecular weight ~45 kDa.

    Peginesatide does not induce any cytochrome P450s and according to in-vitro protein-binding studies does not bind serum albumin or lipoproteins. The half-life of Peginesatide following intravenous administration is 25.0 ± 7.6 hours in healthy subjects and 47.9 ± 16.5 hours in dialysis patients. Clearance is 0.5 ± 0.2 mL/hr.kg and the mean volume of distribution is 34.9 ± 13.8 mL/kg. Peginesatide is mainly cleared through the urine and a study using radio-labelled Peginesatide indicates that it is not excreted unchanged.

    Peginesatide has a black box warning and adverse reactions include increased risk for death, myocardial infarcts, stroke, venous thromboembolism, thrombosis of vascular access and tumor progression or recurrence.

    An advantage of Peginesatide over other ESAs is that it can be administered at monthly intervals. Given the adverse reactions, the dosage recommendation is to individualize dosing and give the lowest dose that is sufficient to reduce the need for blood transfusions. 0.04 mg/kg is the recommended dose for probing patient response.

    Peginesatide was developed by Affymax and Tekeda Pharmaceuticals and is marketed under the trade name Omontys.

    Full prescribing information can be found here.

  • My Morel Guardian


    It's the time of year when every 47 year old man's fancy turns to morels. On campus there is one spot where they grow, and since they are so yummy and scrumptious, I have taken the precaution this year of appointing a 'morel guardian' - Gerard Klewygt. He can keep watch from his desk, tipping me off if anyone spends a suspiciously lengthy time in the bushes.


  • Target Discovery Institute, Oxford, UK.


    I came across a link to the new Oxford Target Discovery Institute today the website is http://www.tdi.ox.ac.uk/home and it contains the BHF Centre for Cardiovascular Target Discovery.  It looks a great new facility, and a significant strengthening of the UK academic armamentarium for drug discovery!

  • Structure-Based DrugEBIlity Webinar 4th April

    This is a call for people wanting to sign up for the "Structure-Based DrugEBIlity" webinar that will be hosted next Wednesday 4th April at 3.30pm (GMT). It will be a 45 minute webinar where you will be taken through our DrugEBIlity interface. The DrugEBIlity interface is a structure-based druggability search engine where users can survey different types of druggability scores of a given protein structure. Remember to register your interest in our webinars on the Doodle Poll. Make sure that you leave your **email address** as well as your name so that we can send the connection details to you. Any problems, please contact chembl-help@ebi.ac.uk.

  • Blogging from the ACS


    I'm at the ACS in San Diego this week, there are three of the ChEMBLites here - two talks down, one to go. It's been a really great meeting, really excellent. I've even managed to sort of stay on UK time, so waking up at about 2am, and then having a good session on the computer before talks start at 8am. My only moan has been that on the computational side, there are too many interesting parallel sessions, and it's difficult to choose where to go. Anyway, I've spent some time with old and new friends, and feel really upbeat about the way that chemoinformatics is impacting our understanding of biology, and how progress is being made in how to design compounds that modulate biological systems. I sense that the availability of large-scale data and large-scale computing are really feeding off each other and allowing things to be developed that could only be imagined a few years ago.

    And in a great advance for mankind, internet is free at the conference; seriously well done ACS for sorting this out - I'm fed up of paying serious cash for internet access at conferences.

    Blogging really seems to have taken off this year - or at least I'm starting to track live blogging more than I did - Rajarshi Guha of NCTT has been a superstar - here's his twitter feed. A must follow account for those in the field.

    Also great has been Carmen Drahl of the ACS itself - here's her twitter feed. Of particular note is the live-blogging she did on first time med. chem. disclosures. Great service - here's the link to the CEN hosted blog. I think there is a great opportunity here to help the world - crowd sourcing and immediately distributing key facts, Carmen has naturally focussed on the chemical structure aspects; but imagine if there were more like-minded people who captured this sort of really valuable data and tweeted or blogged as a community, in a way that others not able to be there could react to the data, analyse it and integrate in their research. If done right, and more importantly could be integrated into a living public and fully Open resource. If the world was even more perfect, the presenters would immediately post their slides online, with semantically marked up assays and InChIs of all the compounds.... hey, you can tell I'm in California!

    The ACS tattoo above is pretty cool; maybe if you ask me nicely when we meet, I can show you mine.

  • Update on EMBO Chemical Biology 2012



    The 2012 EMBO Chemical Biology meeting to be held in Heidelberg is looking very good, we had an excellent set of speakers, and now this has been further strengthened with the presence of George Whitesides.  Links to the conference details are here, registration is now open. We are coordinating some arrangements with the MIPTEC conference in Basel this year, and will set up a daily rate to allow attendees at MIPTEC to participate in the drug discovery sessions at the EMBO meeting. Look in a few days on the conference website for more details of this.

    Of course, several of the ChEMBL group will be there, and so if you'd like to meet any of us there, hear about our plans for the databases, or know more about research, drop us a line.

  • Crowdsourcing for scientific tasks


    I was at a great meeting this week, and there was a discussion of the potential use of crowdsourcing to solve scientific problems, more specifically to generate good ideas for consideration by a panel. There are many successful examples of where many 'different pairs of eyes', 'wisdom of the crowd', 'diverse viewpoints and cultures', etc can solve problems, efficiently. A nice example that I am free to talk about is the recent Sequence Squeeze competition organised by the Pistoia Alliance (google will find some links, I'm under domestic pressure to be quick with this post and make the morning coffee!).

    However, I was struck at just how complex this is to implement in a field where intellectual property (IP) is one of the likely outcomes, and potentially even more so when a prize of some sort is involved. Some of the risks are:

    • Contractual restrictions of participants (for all people, academics, industrialists, etc) - my contract has clear restrictions of what I can and can't do, unpaid or not, for someone else - these are fair I think, and are a trade I have made in order to receive a regular salary in return for doing a job I love. There is a difference of course if it is outside of your professional field and that of the crow sourced problem - coming up with ideas for new fishing hooks for me, would not likely cause problems, whereas IE approaches for biological data mining most certainly would. Employment contracts are different, but if you are interested in participating in anything like this, I would 1) Check your contract, and 2) Tell your employer, and get permission (written) that what you are doing is fine and approved.
    • Restrictions on the literature/software/database licenses - it is likely that for crowdsourced scientific problems, you will need access to 'licensed' materials (your library, software and maybe databases) will be used and/or required. The terms of these licenses are often quite complex, and you may not even know what they are (as an admission, I have never checked out the terms of use of some of the library material we have; however, I know what is typical, and I would like to think of myself as sensible and cautious on these matters). However, it is the case, that typically they do not allow giving stuff away freely to third parties, or even application on 'commercial' activities. So check the terms of any licenses for software/websites/journal access, etc out, and make a copy of this, keep it with your personal records.
    • Risks of accidental or deliberate IP poisoning of the solution - this is pretty significant and potentially very costly and time wasting - imagine you have a participant that is either malicious, or unthinking (the most dangerous is a combination of both features), and gives you some of their employers IP or trade secrets that are useful in solving the challenge. This is a big problem - what if you start work on the basis of this fantastic idea and contribution, and then are served with a cease and desist letter - what are the liabilities. It's actually quite difficult to protect yourself from this, a simple waiver that says that all submissions are given freely and licensed without restriction is simply not good enough. Seriously. Related to this, I would also be really wary where there is the ability or desire to have anonymity on submission.

    So, the likely outcome for well organised crowdsourced things is that the level of legal documentation and protection required for both organisers and participants is likely to be very significant. If anyone knows of any well constructed systems that are fair and balanced in risks to both participants and organisers please let me know.

    I'm sure there's many more issues I haven't thought of, so post away in the comments if you want.