• Choice of chemical sketchers now available within ChEMBL


    There are a lot of excellent chemical sketchers available, and we have now implemented a choice of three within the ChEMBL interface - JME Molecular Editor, Jdraw and MarvinSketch. These three were the three most requested chemical drawing packages, but if there is demand for more please feel free to suggest additional ones.



    Please consider this multi-sketcher capability as still in a test phase, and please report any problems you find.

  • ChEMBL web pages in Japanese


    ChEMBL is now available in a Japanese language form (to access this, just click on the appropriate flag at the top right of the ChEMBL home page).

  • Conference: Joint Sino-UK Protein Symposium, Shanghai, May 5-7 2011


    I have been invited to speak at the Biochemical Society and Chinese Protein Society Joint Sino-UK Protein Symposium being held on the 5th to 7th of May at Shanghai University, China. Some excellent speakers on the agenda, including David Stuart, David Barford, Guy Dodson, and Zhang Youshang. Immunizations and visa office here I come!

  • The ChEMBL Group, Staff and Funding (Jan 2011)

    I've put together some slides for an internal meeting, and I thought they may be interesting to the wider world, maybe.

    The ChEMBL group currently has fifteen staff located at the EMBL-EBI. We perform both 'Service' and 'Research' work within the group, with the distribution plotted below. The total service resourcing is 9.8 people (65% of staff), with the majority directed towards development and support of the various  ChEMBL resources. (All numbers refer to number of staff positions)


    The breakdown of funding sources for the group are as follows. 

     

  • New Drug Approvals 2011 - Pt. III Ioflupane 123I (DaTSCANTM)










    ATC code : V09AB03

    On January 14th 2011, the FDA approved Ioflupane 123I (USAN: Ioflupane I123 USAN date: 2009 tradename: DaTSCAN, NDA 022454)) for the imaging of dopamine transporters in the brain of adult patients with potential Parkinsonian Syndromes. Ioflupane is a radiopharmaceutical agent intended for use with single photon emission computed tomography (SPECT) imaging, to help physicians differentiate essential tremor, from tremor due to Parkinsonian Syndromes.

    Ioflupane 123I binds to, and allows imaging of, the Dopamine Transporter (DaT) (Ki = 0.62 nM IC50 = 0.71 nM). Synonym:SLC6A3 UniProt:Q01959 Pfam:PF00209). Variation or malfunction of the Dopamine Transporter is linked to many neurological and psychiatric disorders.
    The chemical structure of Ioflupane (IUPAC: methyl(1S,3S,4S,5R)-8-(3-fluoropropyl)-3-(4-iodanylphenyl)-8-azabicyclo[3.2.1]octane-4-carboxylate PubChem: CID3086674) is a tropane derivative; tropanes are a class of natural product alkaloids found in a large number of plant species, notable members of this chemical class include cocaine and atropine (a.k.a. hyoscyamine). Therefore Ioflupane is a natural product derivative. The molecular weight is 427.3 Da, with a relatively large fraction of that coming from the single iodine atom (126.9 Da for 'normal' iodine). The calculated logP is 4.0 and Ioflupane contains no hydrogen bond donors and six hydrogen bond acceptors. Ioflupane is therefore fully compliant with Lipinski's rule of five. Other relevant molecular descriptors include a polar surface area of 29.5 Å2 and the molecule contains 6 rotatable bonds. The iodine in DaTSCAN is the radioactive isotope 123I, which has a half-life of 13.2 hr, and decays with emission of gamma rays, it is these gamma rays that are imaged, showing the location of the DaTs in the brain.

    Ioflupane 123I is dosed intravenously, with a total recommended dose in the range 111 to 185 MBq.

    Ioflupane (123I) is cleared from the blood after intravenous (iv) injection, with only 5% of the administered activity remaining in whole blood  5 minutes post-administration. Uptake in the brain is rapid, reaching about 7% of injected activity 10 minutes post-administration, then decreasing to ~3% after 5 hours. By 48 hours post-injection, ~60% of the injected radioactivity is excreted in the urine, with faecal excretion calculated at ~14%.

    The license holder for DaTSCAN is GE Healthcare, the product website is here, and the full prescribing information can be found here (DaTSCAN was approved in the EU in 2007, the European SPC can be found here).

  • New Drug Approvals 2011 - Pt. II Vilazodone hydrochloride (ViibrydTM)











    ATC code (partial): N06A

    On January 21st 2011, the FDA approved Vilazodone hydrochloride for the treatment of major depressive disorder (MDD) (research code: EMD-68843, tradename:Viibryd) (NDA 022567). MDD is a mental disorder believed to arise from abnormal levels of neurotransmitters (primarily serotonin) in the central nervous system. Symptoms are of broad spectrum and typically include depressed mood, fatigue, change of appetite and weight and suicidal thoughts, or attempted suicide. There are already a large number of therapeutics available for the treatment of MDD including the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (ChEMBL41), sertraline (ChEMBL809), paroxetine (CHEMBL569172) and more recently escitalopram (CHEMBL1508). A number of other mechanisms have been explored for treatment of depression, including drugs such as against the serotonin receptor 5HT1A - such as buspirone (research code:BMS-528215, tradename:BuSpar)CHEMBL49) and flesinoxan (clinical trial phase only). Vilazodone however is the first SSRI that also is a partial agonist of 5TH1A (and as such show designed and intended polypharmacology).

    Brain function relies on the transmission and regulation of excitatory and inhibitory signals at the synapses of nerve cells. Upon activation, a presynaptic neuron releases neurotransmitters into the synaptic cleft which in turn activate or inhibit the postsynaptic neuron by binding specific receptors. One of the neurotransmitters with excitatory effects is the biogenic amine serotonin (CHEMBL39, CHEBI:28790). After its release from the presynaptic neuron, Serotonin transmits an excitatory signal and is then removed from the synaptic cleft by an uptake mechanism involving the sodium dependent serotonin transporter (SERT) (Ki 0.1nM Uniprot:P31645 Pfam:PF00209). SERT is a member of a very important family of drug targets including the analogous norepinephrine transporter, other pharmacologically important ligands that have related transporters include GABA, dopamine, amino-acids and so forth) Vilazodone is selective for serotonin over the norepinephrine (Ki 56 nM UniProt:P23975) and dopamine transporters (Ki 37 nM UniProt:Q01959). Inhibition of serotonin reuptake with SSRIs leads to increased levels of serotonin in the synaptic cleft and is used in the treatment of MDD to compensate for the lower homeostatic levels of serotonin in MDD patients compared to healthy individuals. The exact mechanism by which this helps MDD patients is not clear but involves long-term desensitization of presynaptic serotonin receptors which are part of a negative feedback loop in the biosynthesis of serotonin. In addition to it's effects as an SSRI, Vilazodone is a partial agonist of the 5HT1A receptor (IC50 2.1 nM, Uniprot:P08908, Pfam:PF00001, ChEMBL:214) (and selective over the related 5-HT1D, 5-HT2A, and 5-HT2C receptors). However the net result of this partial action on serotonergic transmission and its role in Vilazodone’s overall antidepressant effect are unclear. The 5HT1A receptor is a rhodopsin-like G-protein-coupled receptor (GPCR), the largest single family of historically successful drug targets.




    Vilazodone (IUPAC: 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide
    InChI: 1S/C26H27N5O2/c27-16-18-4-6-23-22(13-18)19(17-29-23)3-1-2-8-30-9-11-31(12-10-30)21-5-7-24-20(14-21)15-25(33-24)26(28)32/h4-7,13-15,17,29H,1-3,8-12H2,(H2,28,32)
    SMILES: NC(=O)c1oc2ccc(cc2c1)N3CCN(CCCCc4c[nH]c5ccc(cc45)C#N)CC3 ChemSpider: 5293518 Chembl:439849) is a synthetic organic molecule with no chiral centers and a molecular weight of 441.5 Da (for the free base) and a calculated LogP of 4.54. With 7 hydrogen bond acceptors and two hydrogen bond donors it is therefore fully compliant with the Lipinski Rule of five. The 7 rotatable bonds make Vilazodone a rather flexible compound. The physical chemistry will be dominated by the basic center in the piperazine ring.

    The pharmacology of Vilazodone is largely due to the parent, dosed drug, and due to the long terminal half life of 25 hr (elimination is largely hepatic), steady state plasma levels are reached after about three days. The mean Cmax value is 156 ng/mL, and the mean AUC (0-24 hours) value is 1645 ng·h/mL. Tmax is around 4.5 hr post administration. Vilazodone is widely distributed and approximately 96-99% protein-bound. Vilazodone is extensively metabolized in the liver through CYP and non-CYP pathways with major contributions from CYP3A4 (Uniprot Id: P08684). The non-CYP route is believed to open via liver carboxylesterase (Uniprot Id: P23141). The absolute bioavailability of vilazodone is 72% with food - Vilazodone shows a large food effect, and if taken without food, bioavailability is significantly lower.

    Vilazodone is administered orally at a typical dose of 40 mg once daily (equivalent to a daily dose of ~83.6 uM of Vilazodone). At start of therapy, the drug is titrated, starting with 10mg once daily over the course of seven days followed by 20 mg once daily over another 7 days before the full dose of 45 mg per day is administered.

    Many drugs of this general class have inherent safety issues, and Vilazodone has safety risks associated with the induction of suicidal thoughts in young adults, adolescents and children. Vilazodone is not approved for the treatment of depressive disorders in children. Viibryd has a boxed warning.

    The full prescribing information is found for Vilazodone here.

    The license holder is Clinical Data and the product website is http://www.viibryd.com/.

  • ChEMBL visit New York March 2011


    Some of us are travelling to New York on business the week of 21st March 2011. We have some space in our schedule for portions of Tuesday the 22nd and Wednesday the 23rd, so if there is interest in meeting up for a coffee, a small seminar on ChEMBL, some training, etc., let me know. We'll probably stay somewhere on the upper East Side, but would be happy to travel to you to meet up.

  • Social Networks



    LinkedIn have a cool new plugin, that plots and clusters your LinkedIn connections, quite a nice illustration of biological network structure and complexity. It doesn't label the clusters for you, but it is easy to assign labels by just looking at a few nodes of each colour. One downside is that you need to have a pretty 'complete' profile in order to build the map. Almost certainly I gave the plugin power of attorney and complete access to all my finances in order to plot this, but it's a pretty picture.....

    Update: The labels I gave were a little simplistic - the blue nodes are really scientific IT and software, the green nodes are better described as large pharma, and the orange nodes as academics/bioinformatics.