New Drug Approvals 2013 - Pt. XV - Vortioxetine Hydrobromide (BrintellixTM)

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.

Paper: Target Prediction for an Open Access Set of Compounds Active against Mycobacterium tuberculosis

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

jpo

ChEMBL Web Service Update 2: JSONP Support

We posted earlier in the week about some behind the scenes changes we had made to our Web Services. Having read that post (if you missed the post and use our Web Services please take a look), you will know we setup a temporary base URL to allow users to test the new ChEMBL API powered services. The base URL is:

https://www.ebi.ac.uk/chemblws2

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:

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL941.json

To create a JSONP response you add the callback argument parameter (Note, you do not need to include .json and the callback argument can be any value):

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL941?callback=chembldata

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

The ChEMBL Team

ChEMBL Virtual Machine (a.k.a. myChEMBL)

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:

ftp://ftp.ebi.ac.uk/pub/databases/chembl/VM/myChEMBL/current/

To install myChEMBL you will need to use some virtualisation software, such as VirtualBox or VMware Fusion. You will find installation instructions on the ftpsite, which describe how to load myChEMBL into VirtualBox. These will soon appear on this blog - with pictures :)

Get in touch via mail to chembl-help@ebi.ac.uk if you have any myChEMBL questions.



The ChEMBL Team

Compound Curation - The story so far...

As chemical curator for ChEMBL, I spend a lot of time
processing, checking and standardising the compounds in the database. I
use various pieces of software for this, but mostly it’s Pipeline Pilot. For
those of you who don’t know, Pipeline Pilot is Accelrys’s graphical scientific
workflow authoring application, that allows passing hundreds of thousands
of compounds through various components to make sure they meet our standards to
be loaded into ChEMBL.

However, it’s always incredibly useful to utilise other available software in a complementary manner to see if anything
may have been missed, could be done in a different way or just to see what alternative results
you can get. One such open source software package is Indigo, created by GGA Software Services. On of the web
application developers was passing all of the ChEMBL compounds through
the standard Indigo loader, via a Python script, during the course of his work, and found that there
were about 9,000 compounds (0.7% of the current database) that failed to be loaded. The list of exceptions was then examined to see where the errors had come from. An important learning here is that different tool kits will throw different exceptions, since these structures were all happy within the PP environment.

The reasons
they had failed were as follows:

1. The presence of a wiggly (query) bond

2. Two stereo bonds connected to one chiral centre

This was split into two sections:

Firstly, where the two bonds effectively
canceled each other out and no stereochemistry was recorded at that centre.

Secondly, where the stereochemistry was present
at that centre but having the two stereo bonds is against IUPAC drawing standards.

3. Presence of a stereo bond when there’s no chiral centre

Some examples of typical scenarios are shown below:

From this Indigo check, I was able to extract and fix these compounds, a lot of which won’t have new standard InChIs, just updated molfiles (i.e. they will keep their CHEMBL ID). For most of these compounds, to confirm the changes that I was going to make, I went back to the original published literature. It is interesting to note that the majority of compounds with the two stereo bonds on a single chiral centre had been extracted exactly as they had been drawn in the paper. 

These changes will be visible in ChEMBL_18 and I am aiming to
incorporate this Indigo loader into our standard compound cleanup and loading protocol. This will probably be implemented under the Indigo toolkit extension that is found in Knime.

Any questions or queries about what I have done, please feel free to
email: Chembl-help@ebi.ac.uk

Louisa

Faculty positions for Bioinformatics and Computational Biology - The Crick Institute, London

An outstanding opportunity for computational research using approaches such as bioinformatics, genomics, systems biology, mathematical modelling, image analysis.

The Francis Crick Institute  http://www.crick.ac.uk

The Francis Crick Institute will open at St Pancras in central London in 2015. Its research will use interdisciplinary approaches to investigate the biology of human health and disease, supported by core funding from CRUK, the MRC, and the Wellcome Trust, and by grants from UK and international funding agencies.

The Crick is expanding Computational Biology research as a key component of its scientific strategy. The institute will offer an outstanding environment for computational research, with excellent opportunities for wet/dry collaborations across the range of biomedical and clinical research disciplines, supported by a strategic alliance with the Wellcome Trust Sanger Institute. The new Crick laboratories will feature excellent computational facilities including a state-of-the-art data centre.

The London Research Institute  http://www.london-research-institute.org.uk

The London Research Institute (LRI) is the largest Cancer Research UK research institute, with 40 research groups focusing on fundamental cancer biology. The Institute is based in well-equipped laboratories at Lincoln's Inn Fields in central London, and at Clare Hall in Hertfordshire.

Computational Biology in Cancer http://tinyurl.com/ohgnxw8
An outstanding opportunity for computational research using approaches such as bioinformatics, genomics, systems biology, mathematical modelling, image analysis. The LRI recruitment process for 2013 will carried out jointly with the Crick Institute. We shall appoint outstanding scientists seeking to establish independent and innovative research programmes focussed on: 

Newly appointed group leaders will receive core funding for research personnel, travel and consumables, and access to the Institute's comprehensive computational core facilities, backed by competitive employment terms. The new group leaders will move to the Crick laboratories in 2015.

Website: http://tinyurl.com/ohgnxw8

Application deadline: 22 November 2013

ChEMBL Web Service Update 1

Over the last the year we have be doing a lot work designing and building an API layer to the ChEMBL database. The reason for adding this programmatic interface is to simplify many of the daily tasks we carry out on the database. From a technical perspective the API is actually a series Object Relational Mapper (ORM) classes built on top of the ChEMBL database using the Python Django web framework. For many of our daily programmatic tasks we use the ORM directly, but we also expose the ORM as a RESTful Interface using Tastypie.



Some examples tools and processes currently using the new API include the ChEMBL twitter bot and the database migration process (creating PostgreSQL and MySQL versions of the ChEMBL Oracle database during the ChEMBL release cycle). We are now at the stage where we can start to think about updating some of the existing larger services to run off the new API and first of these to make the transition are the ChEMBL Web Services. So, what have we done? Essentially we have rewritten the Web Services using the API (actually we use the ORM in this case) to interact with the ChEMBL data model. We have made this new set of Web Services available under the following base URL:

https://www.ebi.ac.uk/chemblws2

Those familiar with our current Web Services will notice we have added a ‘2’, to the end. An example call the current live service looks like:

https://www.ebi.ac.uk/chemblws/compounds/CHEMBL1.json

and the same call to the new Web Services looks like:

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL1.json

To refresh yourself on all methods we currently make available please visit the Web Service Documentation page



The new Web Service base URL will provide you with all the same methods listed on page above and more importantly the format of the results returned by the Web Services will also be the same. Our plan going forward is to run both services for next 4-6 weeks and we ask users of the current ChEMBL Web Services to test the new versions (remember you just need to add a 2) and report back any issues encountered. Assuming we do not hit any major obstacles, after the 4-6 week period we will replace the current live services with the new ChEMBL API based services.



This first Web Service update is technology focused. We want to ensure the new services scale and perform well in the wild and that our end users do not notice a change (well we are hopefully expecting you to see a performance boost). Further down the line we will make some bigger changes to the Web Services, such as reviewing methods, attributes, naming conventions, introduce paging and more. We will obviously consult the community and allow for a period of transition before releasing any such changes. Now is the time to tell us if you have any must have new ws features.



Finally, it is not strictly true that the new Web Services are identical to the current live versions. There are a couple of new features we have built in, such as improved image rendering and JSONP responses. We will blog about these in new features in the next couple of days, but in the meantime please have a look at new ChEMBL Web Services and let us know how you get on.



The ChEMBL Team