• USAN Watch - August 2011

    The August 2011 USANs have just been published.

    USAN Research Code
    Structure    		Drug Type Drug Class Target
    flanvotumabIMC-20DS7monoclocal antibodytherapeuticgp75
    glycerol phenylbutyrateHPN-100synthetic small molecule prodrugtherapeuticn/a
    orteronelTAK-700synthetic small molecule drugtherapeuticsteroid 17-alpha hydroxylase/17,20 lyase
    plazomicinACHN-490natural product-derived drugtherapeutic30S ribosome
    radavirsenAVI-7100oligonucleotide derivedtherapeuticInfluenza virus
    rasagilineTV-1030synthetic small moleculetherapeuticMAO-B
    romosozumabAMG-785monoclonal antibodytherapeuticsclerostin
    setrobuvirANA-598synthetic small moleculetherapeuticHCV polymerase
    sutezolidPNU-100480, PF-02341272 synthetic small moleculetherapeutic50S ribosome
    tozadenantSYN-115, RO-4494351synthetic small moleculetherapeuticA2a receptor
    trelagliptinSYR-472synthetic small moleculetherapeuticDPP-4
    trebananibAMG-386antibody derivedtherapeuticangiopoietin1/2
    umeclidinium, umeclidinium bromideGSK-573719, synthetic small moleculetherapeuticmuscarinic receptors

  • Drug Repurposing: Screening of known drugs against malaria


    Just a quick (but surprisingly wordy) follow up on the previous post on the drug profiling against malaria. Drug repurposing/reuse/rescue offers great potential for the enhancement of patient lives and also is a quick way of pushing new therapies through the clinic. It is often see as low cost and low risk, is highly translational in terms of the research, and there are some stunning success stories. It is therefore very sensible to screen known drugs in assays of interest, which is exactly what was done in the recent, excellent, Science paper.

    The compounds in Table 1 of the paper are reported at the highly active set (and these exclude already known established antimalarial drugs which all pass the selection criteria used for compounds in this table, this seems a pretty good and pragmatic place to set cutoffs). For use as an widely-used and developing world-applicable antimalarial (co)-therapy I would have imagined that ideally you would want established well tolerated daily dosing, since existing malaria therapies are oral and have (generally) good tolerability.

    So, for this list of 32 drugs, a quick internet-based classification was done - factors analysed included:
    1. whether the drugs were already approved for human use 
    2. the dosage/absorption route
    3. any special monitoring requirements (there is probably no option for dose titration/liver monitoring for the vast majority of malaria victims). 
    The results are interesting, and a little sobering.

    Of the 32, I could find (using a flaky internet connection from the my holiday sun-chair) data that looked OK on 30 (the ones I couldn't easily find things on were suberoylanilide and Alazanine triclofenate - if others know anything, post something in the comments). Of these 30, five (20%) are currently animal use only, nine (30%) are IV use only, one (3%) is not currently approved in humans or animals (Lestautinib), and eight (27%) are topical/inhaled use only. This leaves six (20%) that have the desired profile of being orally dosed and currently approved for human usage. Of these, four have restrictive use/or appear to be poorly tolerated (for example, fumagilin is hospital use only and requires careful monitoring). So this leaves two reasonable candidates for first pass consideration as real 'drug-repurposing' candidates - Dextroamphetamine saccharate and orlistat.

    Dextroamphetamine will clearly have regulatory and huge misuse potential, so is also probably a non-starter, regardless of any PK/exposure concerns; so Orlistat then? Orlistat is used as an over-the-counter (in some territories) and prescription drug to assist with weight loss. If works by reducing the absorption of fat from the diet, leading to a variety of side effects - there is much discussion on the safety and side effects (google will find a lot of comment), so in populations that are in malaria endemic regions, a drug that could be dosed to underweight malnourished patients and that reduce the absorption of a key food group (and also most fatty essential vitamins) may not be optimal. A larger issue though is that orlistat works in the lumen of the stomach and intestine, where the target human enzyme is secreted, so for obesity treatment, orlistat does not need to be absorbed into the rest of the body, and it isn't. So, ignoring the side effects for a moment, the negligible systemic exposure of orlistat again probably precludes its use as an antimalarial.

    It will be interesting to me if this sort of pattern of results, and the importance of considering in vitro to in vivo translation for 'known drug' screening is typical. Sorry for the long post - thoughts, comments and discussion most welcome.

    Update: Looking at the supplementary material for the paper - it seems likely that suberoylanilide from table 1 is actually suberoylanilide hydroxamic acid (aka Vorinostat, or Zolinza). This is an oral drug for the treatment of certain refractory cancers, it can give rise to a wide range of serious side effects that would almost certainly preclude widespread non-supervised use (at least at the doses used for current indications).

    Update 2: Thanks to the authors for confirming that the suberoylanilide should be SAHA, and also for confirming that Alazanide triclofenate is an unusual compound with not a lot of current published literature.

  • ChEMBL 11 Released

    We are pleased to announce the release of ChEMBL_11. This latest version of the ChEMBL database contains:
    • 1,195,368 compound records
    • 1,060,258 distinct compounds
    • 582,982 assays
    • 5,479,146 activities
    • 8,603 targets
    • 42,516 documents
    • 7 activity data sources
    You can download the data from the ChEMBL ftpsite: ftp://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/latest/ Changes to the data and database include:
    • The loading of the quantitative activity data from the Guide to Receptors and Channels (4th Edition)
    • Updating of the organism classification information
    • The ChEMBL identifiers for all previous compounds/assays/documents/targets within the database, including those that have been removed/downgraded are now maintained within the chembl_id_lookup table
    For a full and more detailed list of changes to the data and database please refer to the release notes. Changes to the interface include:
    • The ChEMBL widgets have been updated. The example widget below displays the molecular weight distribution of compounds that bind to human ABL1. (Note, the widget will now load external JavaScript dependencies, so you can easily add it to blog posts like this and target based widgets now accept UniProt accessions) Further details about the widgets can be found here https://www.ebi.ac.uk/chembl/widget

  • Deadline for ESPOD Project on Malaria Target Discovery Is Approaching....


    The deadline for applications to the exciting Rayner/Overington project on malaria target discovery is fast approaching - for details of the project, see here. The deadline is Monday 15th August 2011.

  • Descriptors for Protein Sequences?


    Does anyone know of a website/web service that calculates a series of descriptors of a protein sequence, analogous to the descriptors that are regularly calculated for small molecules.

    Specifically what I'm looking for is something that gives a large set of descriptors for either a sequence, or for a given stable identifier (e.g. UniProt ID). The descriptors I'd like back would be things like Molecular weight, number of each amino acid, fraction of each amino acid, hydrophobicity values, complexity/sequence entropy values, number of transmembrane helices, presence of certain features (e.g. signal sequence, nuclear localisation sequence, etc.), domain counts would be good as well - building up a 'fingerprint' for the sequence. I guess with a little bit of thought, it would be possible to come up with a fuller list of descriptors, and the above certainly isn't exclusive, but you get the idea; I'm sure. To be clear, I don't want an annotation service, I just want some numerical/logical feature descriptors.

    Does something like this exist, should it be built if not, and so forth?

  • Papers: Chemical Genomic Profiling for Antimalarial Therapies, Response Signatures, and Molecular Targets



    There's a really interesting paper just published in Science on the screening of the NCGC drug collection against the malaria parasite, it's a tour de force in the application of screening and genomics analysis/exploration of bioactivity data. Amongst the 32 highly actives there are mostly cytotoxic agents, which are probably no big surprise, but a couple of interesting things in there, more later on this (probably...)

    Anyway the paper is here.

    %T Chemical Genomic Profiling for Antimalarial Therapies, Response Signatures, and Molecular Targets
%J Science
%V 333
%P 724-729
%D 2011
%A J. Yuan
%A K.C.-C. Cheng
%A R.L. Johnson
%A R. Huang
%A S. Pattaradilokrat
%A A. Liu
%A R. Guha
%A D.A. Fidock
%A J. Inglese
%A T.E. Wellems
%A C.P. Austin
%A X.Z Su

  • GPCR Structures - Ternary complex of β2AR and Gs heterotrimer


    The latest GPCR structure, published in Nature, adds further to our understanding of the detailed conformational changes that lead to signal transduction for the rhodopsin-like GPCRs - specifically the structure of the active state ternary complex of agonist-activated monomeric β2AR and nucleotide-free Gs heterotrimer. As in most other GPCR structures, engineering of the receptor was performed, and the structure also contains an antibody derived fragment, and an inserted lysozyme domain within the β2AR chain.

    Coordinates are accessible at PDBe:3sn6, ligand data is at CHEMBL:1615159

    %T Crystal structure of the β2 adrenergic receptor–Gs protein complex
%A S.G.F. Rasmussen
%A B.T. DeVree
%A Y. Zou
%A A.C. Kruse
%A K.Y. Chung
%A T.S. Kobilka
%A F.S. Thian
%A P.S. Chae
%A E. Pardon
%A D. Calinski
%A J.M. Mathiesen
%A S.T.A. Shah
%A J.A. Lyons
%A M. Caffrey
%A S.H. Gellman
%A J. Steyaert
%A G. Skiniotis
%A W.I. Weis
%A R.K. Sunahara
%A B.K. Kobilka
%J Nature 
%D 2011
    %V 477
    %P 549-555
%O doi:10.1038/nature10361

  • Meetings: SMR Recent Disclosures of Clinical Candidates


    One of the best UK meetings I try to go to is the annual Society of Medicines Research (SMR) meeting on recent clinical candidates. This year, it is being held on Thursday 8th December 2011, the the NHLI in London, further details are here. Compounds covered include: OSI-906, AZD-4547, fostamatinib, POL-7080, and AFQ-056, amongst others.