EU-OPENSCREEN 3rd Stakeholder Meeting, Oslo, Norway

Dear future user, partner, collaborator or supporter!

The ESFRI project EU-OPENSCREEN is an academic infrastructure initiative in Chemical Biology to serve your research needs. We are currently preparing the implementation of this pan-European infrastructure of open screening platforms to support basic and applied research. EU-OPENSCREEN will offer access to a unique compound library representing the know-how of European chemists, to a broad range of cutting-edge screening technologies, to valuable tool compounds for research, and to the knowledge that emerges from validated output of hundreds of screens stored and made publically available in a central database.

We cordially invite you to join us in Oslo for an exciting science day where we inform about the progress of the project and the planned services with reports on the design of the joint European Compound Library, the screening services and the database. In particular, we would like to share with you your own experiences from academic screening projects and thus invite you to present your projects as poster. From these, highlight projects will be selected for oral presentation.

See http://www.eu-openscreen.eu for more details.

Competition Time - Win a Raspberry Pi with ChEMBL - chempi

Here's a free to enter competition for a brand new, fully working raspberry pi running the brand new chempi implementation. It includes everything you need to get started at home with ChEMBL - a sort of in silico Breaking Bad maybe (hopefully not, thinking about it). It includes everything you need, with the exception of a power supply and ethernet cable.



We have run out of our creative juices, and cannot think of a suitable poem to mark the release of chempi - so the competition is for you to finish a limerick for us, starting with the line.



There once was a hacker with chempi....



Entries must be posted in the comments section. Obscene or defamatory entries will be removed (all comments are moderated, so it may take a few hours for you entry to appear, so do not repost twenty times!). We haven't really decided how to pronounce chempi (with a hard 'k' start or a soft 'sh' start, just as with ChEMBL, both are used in the wild; and also does it rhyme with scampi, or the irrational number pi?). All entries will be assumed to be made under CC-BY licensing. The competition will be open until noon GMT on Sunday 10th November 2013.



Entires will be judged for compliance to a standard limerick format, outrageous rhymes with chempi, gratuitous chemistry references, and finally humour.



The judges decision (i.e. mine) is final. The winning entry will be published on the ChEMBL-og.



jpo



PS Before I get asked, the competition is not open to members of the ChEMBL group, or extended family members of the ChEMBL group.

Tastypie & Chempi

One of the immediate consequences of refactoring our webservices using Django, Tastypie and related approaches (as described here) is that we can run them on almost any database backend. Django abstracts communication with database and using custom QueryManagers we were able to implement chemisty-specific opererations, such as substructure and similarity search in a database agnostic manner.



This means, that if we want, we can use only Open Source components (such as Postgres and RDKit), or elect to use optimised commercially sourced software as appropriate. However, what if we go one step further and try to use Open Hardware as well? This is exactly what we've just done! We managed to install full ChEMBL 17 on raspbery pi.



Some frequently asked questions (at lease those that have been asked internally) and technical details are below:



1. How much space does it take?



12 Gb, including OS, data and all relevant software. Unfortunately we a used 32 Gb SD card so this is size if you would like to use our cloned disk image.



EDIT: Compressed image takes 4.13 Gb.



2. What OS is it running?



Raspbian, free operating system based on Debian.



3. Is it slow?



We haven't make any benchmarks yet. Obviously it's slower than our online web services - but then it's a lot cheaper. On the other hand, performing some sample requests we can say that performance is certainly acceptable; and there is a lot room for improvements - raspberry pis can be easily overclocked from 700 MHz to 1GHz and according to some benchmarks this can give rise to doubling of application speed in some cases. The SD card we used is not the fastest one as well. Finally, all caching is disabled because we wanted to save disk space but using database caching from Django caching framework should give further major improvements - so maybe use the 32 Gb image after all.



Types of request that chempi can be slower on are:



 - Image generation, but if we replace image with JSON from which image can be generated using HTML5 canvas on the client side (the way we generated images in our game) it can be much faster. More about this topic in future blog post.

- Queries using aggregate functions such as COUNT (it seems that we need to optimise our postgres db by adding some more indexes).

- Substructure and similarity search - again, caching, over-clocking and some database and cartridge (choosing faster fingerprints) optimization should solve all the problems. "Premature optimization is a root of all evil", so we first wanted to have a proof of concept that just works, not necessarily works super fast.



4. Can I make my own chempi?



Yes, we are planning to share our SD card image, we will probably use BitTorrent protocol to do this due to image size, and some issues we have faced with distribution of the myChEMBL. We do remember that not everyone has mega-fast broadband!



5. Is chempi useful at all?



Although we think it is interesting as a proof of concept having chemical database on such small and open source hardware, we do think this may have some interesting future real-world applications:



 - plugging our chempi to local network makes it immediately accessible to other computers. So this is a zero configuration demonstration of ChEMBL.

- analogically to the thesis included in this paper, it can encourage cheminformatics education on low cost ARM hardware.

- raspberry can be easily enhanced with camera to perform image recognition. This, combined with software like OSRA can give ability so scan compound images and search them in database.

- adding some e-ink display (for example, jailbroken Kindle?) can produce very interesting small machine...



6. What are some of the technical details?



To deploy our webservices (which are just another Django application) we've used Gunicorn as a server, which in turn connects to NGINX via standard unix pipe. To make it work as a deamon and launch on machine startup, we've used Supervisor. We believe this is ideal way to deploy Django not only on raspberry but on all production machines to if you like to run chembl webservices locally in your company/academia we suggest to do it this way.

michal

Usan Watch: October 2013

The USANs for October 2013 have recently been published.



We have modified the sourcing of this data - using the new ChEMBL API to automatically parse the documents, extract and validate the mol files for the compounds. So in future, these reports should be more timely, complete and fun!

USAN	Research Code	InChIKey (Parent)	Drug Class	Therapeutic class	Target
alectinib	AF-802; CH-5424802	KDGFLJKFZUIJMX-UHFFFAOYSA-N	synthetic small molecule	therapeutic	ALK
apitolisib	GDC-0980.1, G-038390, G-038390.1, RG-7422	YOVVNQKCSKSHKT-HNNXBMFYSA-N	synthetic small molecule	therapeutic	MTOR,PI3K
cimaglermin-alfa	GGF2, rhGGF2	n/a	protein	therapeutic	ErbB
decernotinib	VX-509, VRT-831509	ASUGUQWIHMTFJL-QGZVFWFLSA-N	synthetic small molecule	therapeutic	JAK3
elobixibat	A-3309; AZD-7806	XFLQIRAKKLNXRQ-UUWRZZSWSA-N	n/a	therapeutic	SLC10A2
ipatasertib	GDC-0068; RG-7440	GRZXWCHAXNAUHY-NSISKUIASA-N	synthetic small molecule	therapeutic	AKT
lixisenatide	AVE-0010	n/a	peptide	therapeutic	GLP1R
ulocuplumab	MDX-1338, BMS-936564	n/a	monoclonal antibody	therapeutic	CXCR4

New Drug Approvals 2013 - Pt. XVII - Macitentan (Opsumit ®)

ATC Code: C02KX (imcomplete)

Wikipedia: Macitentan

ChEMBL: CHEMBL2103873

On October 13th the FDA approved Macitentan (trade name Opsumit ®) for the treatment of pulmonary arterial hypertension (PAH). Macitentan is an endothelin receptor antagonist (with affinities to both Endothelin ET-A (ETA) and Endothelin ET-B (ETB) receptor subtypes, similar in mechanism of action to the previously licensed drug Bosentan, CHEMBLID957).

Target(s)

The Endothelin receptor ET-A (ETA, CHEMBLID252 ; Uniprot P25101) and Endothelin receptor ET-B (ETB, CHEMBLID1785 ; Uniprot P24530) receptors mediate a number of physiological effects via the natural peptide agonist Endothelin-1 (ET1 , CHEMBL437472 ; Uniprot P05305). In addition to normal roles in supporting homeostasis, these effects can include pathologies such as inflammation, vasoconstriction, fibrosis and hypertrophy.



Macitentan acts as an antagonist for both receptors with both a high affinity and long residence time in human pulmonary arterial smooth muscle cells. Hence it counteracts vasoconstriction and relieves hypertension. One of the metabolites of Macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro

Macitentan (CHEMBL2103873 ; Pubchem : 16004692 ) is a small molecule drug with a molecular weight of 588.3 Da, an AlogP of 3.67, 11 rotatable bonds, and 1 rule of 5 violation.

Canonical SMILES : CCCNS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1c3ccc(Br)cc3

InChi: InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)

Dosage

10 mg once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.



Metabolism and Elimination 

Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with a minor contribution of CYP2C19. It is interesting to note the presence of bromine atoms in two of the aryl rings, typically a lighter halogen, typically fluorine is used to block oxidative P450-mediated metabolism at these exposed aromatic positions.



At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces.



Pregnancy

Macitentan may cause fetal harm when administered to a pregnant woman. Macitentan is contraindicated in females who are pregnant.



Hepatotoxicity

Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. Obtain liver enzyme tests prior to initiation of Macitentan and repeat during treatment as clinically indicated.



Hemoglobin Decrease 

Decreases in hemoglobin concentration and hematocrit have occurred following administration

of other ERAs and were observed in clinical studies with Macitentan. These decreases occurred

early and stabilized thereafter Initiation of Macitentan is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.



Strong CYP3A4 Inducers / Inhibitors

Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure whereas concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir (CHEMBL163) are strong inhibitors of CYP3A4.

The license holder is Actelion Pharmaceuticals US the full prescribing information can be found here.

Some Gamification of ChEMBL

Here's a small toy app built from the ChEMBL API - really just a technology exemplar - but also pointing towards some interesting potential crowdsourced things that could be done - for example community classification of the drug-likeness of compounds, or the identification of complex toxicophores - the sort of thing where capturing 'expert' tacit knowledge is needed - and the best way to learn is through analysis of examples.



So, have a play, and see how well you do.



There's a small interesting story behind this app - I originally thought we should do a dirty hack (a mapped gif - the shame of it) - but no, the development pixies, did a proper job, and in a very short time....



The first load of the app is slow. So settle down, clear your mind, and get ready to test your skills. The obvious next feature for this is one of those buttons to tweet a score, saying something like - "I got to level 7 on the ChEMBL-brain-O-thon"



Oh, the url for this won't be stable, and may well disappear completely, so be quick and waste some valuable work time now!



jpo

ChEMBL Web Service Update 3: Image Rendering Changes

If you are a follower of this blog you will have seen some earlier posts (here and here) providing details on changes we are making to our Web Services. I recommend reviewing the previous posts, but in summary we have setup a temporary base URL to allow existing ChEMBL Web Service users to test the new ChEMBL API powered Web Services. The new temporary base URL is:

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

As well as providing users with all existing functionality we have also added a couple of extra features, one of which is improved molecule rendering options. The current live Web Services provides the following REST call to allow you to get a molecule image: 

https://www.ebi.ac.uk/chemblws/compounds/CHEMBL192/image

  

You are able to provide a dimension argument (pixels) to change the size of the image:

https://www.ebi.ac.uk/chemblws/compounds/CHEMBL192/image?dimensions=200

The image quality has deteriorated, this is because the image returned is simply re-sized version of the first image. The new ChEMBL API powered Web Services addresses this issue by dynamically generating the images, using either the RDKit or the Indgio chemistry toolkits (defaults to RDKit). So, to get an image using the new services, you just need to add '2' to the base URL:

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL192/image

 

When using the dimensions argument with the new Web Services you now get the following improved smaller image:

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL192/image?dimensions=200

The coordinates used to generate the image are based on those found in the ChEMBL192 molfile. All current ChEMBL images are produced using Pipeline Pilot, which is currently setup to ignore the molfile coordinates and layout molecule how it sees best. This explains why the layout of the first two images are different to the second two. We can get the new Web Services to ignore coordinates and get the chemical toolkit to layout molecule coordinates how it sees best using the ignoreCoords=1 argument:

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL192/image?ignoreCoords=1

If you would prefer to use Indigo to generate your ChEMBL molecule images you can use the engine argument:

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL192/image?engine=indigo

Finally, it is also possible to use any combination of the 3 arguments mentioned above:

https://www.ebi.ac.uk/chemblws2/compounds/CHEMBL192/image?engine=indigo&ignoreCoords=1&dimensions=200

 

In summary, the new Web Service base URL extends the the current image generating functionality, by improving the dimensions argument and introducing the ignoreCoords and engine arguments. More details in table below:

Argument Name	Argument Description	Argument Options	Default
dimensions	Size of image in pixels	1-500	500
ignoreCoords	Choose to use or ignore coordinates in ChEMBL molfiles	1 or 0	0 (Use ChEMBL molfile coordinates)
engine	Chemical toolkit used to generate image	RDKit or indigo	RDKit

We hope you find these image  rendering changes useful and if you have any questions please let us know via mail to "chembl-help at ebi.ac.uk" if you have any questions.

The ChEMBL Team