ChEMBL

Yes - I'd like a two day course at the EBI next year

Yes - I'd like webinars

Yes - I'd like you to visit our lab (charge involved)

Yes - but not from you guys.

No - Knime, what's that

jpo

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ATC code: not yet assigned

Wikipedia: Riociguat

ATC Code: N06AX26
Wikipedia: Vortioxetine

On September 30th 2013, FDA approved Vortioxetine (as the hydrobromide salt; tradename: Britellix; research code: Lu AA21004 (Lu AA21004 (HBR) for the hydrobromide salt); ChEMBL: CHEMBL2104993), a multimodal antidepressant indicated for the treatment of major depressive disorder (MDD).

MDD is a mental disorder characterised by low mood and/or loss of pleasure in most activities, and by symptoms or signs such as increased fatigue, change in appetite or weight, insomnia or excessive sleeping and suicide attempts or thoughts of suicide. MDD is believed to arise from low levels of neurotransmitters (primarily serotonin (5-HT), norepinepherine (NE) and dopamine(DA)) in the synaptic cleft between neurons in the brain. Several antidepressants for the treatment of MDD are already available in the market and its choice depends on which symptoms need to be tackled. The most important classes of antidepressants include the Selective Serotonin Reuptake Inhibitors (SSRIs) such as Fluoxetine (ChEMBL: CHEMBL41), Sertraline (ChEMBL: CHEMBL809), Paroxetine (ChEMBL: CHEMBL490), Fluvoxamine (ChEMBL: CHEMBL814) and Escitalopram (ChEMBL: CHEMBL1508), which are believed to maintain the levels of 5-HT high in the synapse; and the Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) such as Venlafaxine (ChEMBL: CHEMBL637), Duloxetine (ChEMBL: CHEMBL1175), Desvenlafaxine (ChEMBL: CHEMBL1118) and Milnacipran (ChEMBL: CHEMBL259209), which in turn are thought to maintain higher levels of 5-HT and NE in the synapse. Vortioxetine is a novel multimodal serotonergic compound, which displays antagonistic properties at serotonin receptors 5-HT_3A (ChEMBL: CHEMBL1899; K_i=3.7nM) and 5-HT₇ (ChEMBL: CHEMBL3155; K_i=19nM), partial agonist properties at 5-HT_1B receptors (ChEMBL: CHEMBL1898; K_i=33nM), agonistic properties at 5-HT_1A receptors (ChEMBL: CHEMBL214; K_i=15nM) and potent inhibition at the serotonin transporter (SERT) (ChEMBL: CHEMBL228; K_i=1.6nM). The contribution of these activities to the antidepressant action of Vortioxetine is not fully understood, however Vortioxetine is believed to be the first compound with this combination of pharmacodynamic activity.


Vortioxetine is a synthetic small molecule with a molecular weight of 298.5 g.mol^-1 (379.4 g.mol^-1 for the hydrobromide salt), an ALogP of 4.5, 3 hydrogen bond acceptors, 1 hydrogen bond donor, and therefore fully compliant with Lipinski's rule of five.
IUPAC: 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide
Canonical Smiles: Cc1ccc(Sc2ccccc2N3CCNCC3)c(C)c1
InCHI: InChI=1S/C18H22N2S/c1-14-7-8-17(15(2)13-14)21-18-6-4-3-5-16(18)20-11-9-19-10-12-20/h3-8,13,19H,9-12H2,1-2H3

The recommended starting dose of Vortioxetine is 10 mg administrated orally once daily. The dose should then be increased to 20 mg/day, as tolerated. For patients who do not tolerate higher doses, a dose of 5 mg/day should be considered. Vortioxetine is 75% orally bioavailable, with an apparent volume of distribution of 2600L, a plasma protein binding of 98% and a terminal half-life of ca. 66 hours. Vortioxetine is extensively metabolised primarily through oxidation via cytrochrome P450 enzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalysing Vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite. Poor metabolisers of CYP2D6 have approximately twice the Vortioxetine plasma concentration of extensive metabolisers and therefore the maximum recommended dose in known CYP2D6 poor metabolisers is 10 mg/day. Vortioxetine is excreted in the urine (59%) and feces (26%) as metabolites, with a negligible amount of unchanged compound being excreted in the urine up to 48 hours.

The licensed holder of Vortioxetine is H. Lundbeck A/S and the full prescribing information can be found here.

Here's a paper detailing some multi-method target prediction work as part of the GeMoA FP7 project. Proud, as ever, to publish Open Access.

%A Martínez-Jiménez F
%A Papadatos G
%A Yang L
%A Wallace IM
%A Kumar V
%A Pieper U
%A Sali A
%A Brown JR
%A Overington JP
%A Marti-Renom MA
%D 2013 
%T Target Prediction for an Open Access Set of Compounds Active against Mycobacterium tuberculosis
%J PLoS. Comput. Biol. 
%V 9
%P e1003253
%O doi:10.1371/journal.pcbi.1003253

We have made it straightforward for users to test the new services as all current methods are available using the new base URL. As well as maintaining existing functionality, we have also been able to add a couple of new features, the first of which is JSONP support. Those familiar with web application development will be familiar with the issue of requesting data from a domain different from that of the domain the web application is running. This type of data requested is prevented by the web browser, due to the enforcement of the same-origin policy. This is an important security concept, but there are times when it being able pull data in from a trusted source enhances the functionality of the web application and makes the life of the developer much easier. Adding JSONP support to the ChEMBL Web Services allows users to now pull ChEMBL data into their web pages with minimal effort. So how do you add JSONP support? Simple, you add an extra argument to the to Web Service call which provides the name of a callback function, which is then used to wrap the regular JSON response.

Currently you can request a JSON response with the following URL:

We hope you find this useful and if you have any questions get in touch.

The ChEMBL Team

With last weeks ChEMBL_17 release out of the way, we have had time to revisit our ChEMBL Virtual Machine project. This project, which we now refer to as myChEMBL, is aimed at providing users with a complete and free, easy-to-intstall cheminformatics infrastructure. To achieve this we have provided users with a Ubuntu based virtual machine, which comes with:

• A PostgreSQL database, preloaded with ChEMBL_17. You will notice some extra tables, which are required to allow the RDkit chemical searching.
• The latest build of RDkit taken from the RDkit github repo.
• A web application to allow you to query the ChEMBL database. You can pick up a copy of the web application from Rodrigo Ochoa github repo.

You might now ask How do I get a copy of myChEMBL? And the answer to that is you visit the ChEMBL ftpsite: