ChEMBL Resources

Resources:
ChEMBL
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SureChEMBL
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ChEMBL-NTD
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ChEMBL-Malaria
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The SARfaris: GPCR, Kinase, ADME
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UniChem
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DrugEBIlity
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ECBD

Wednesday, 27 October 2010

Contractor Positions Within ChEMBL


As mentioned in a previous post, we now have some immediately available positions within our team for some short-term contractors (6 months to 1 year). These are for two collaborative (and very exciting) industry projects, and require good bioinformatics knowledge, programming in perl (or equivalent) knowledge of SQL, and database querying and integration. Previous experience in either target assessment, or computational studies of ADMET processes would be greatly beneficial (see below).

One position will be to work on 'druggability' calculations, the second will be connected with comparative genomics of ADMET systems - building a prototype ADMET SARfari (see the SARfari tags on the ChEMBL-og for more details on SARfari). Positions are full time and require a pre-existing right of residence and also pre-existing right to work within the United Kingdom. Pay and general conditions are subject to negotiation. Work will be based at our Hinxton campus site. More details are available on request.

We will post additional information on LinkedIn in a day or so.....

Friday, 22 October 2010

Staff Post in ChEMBL - EU-OPENSCREEN Database developer

We will soon post on the EMBL recruitment pages, details of a new post within ChEMBL - a database developer for a very exciting pan-European collaboration called EU-OPENSCREEN. EU-OPENSCREEN is one of a set of large-scale Research Infrastructure projects called 'ESFRIs', and EU-OPENSCREEN is connected with establishing an infrastructure of screening centers, compound collections and associated 'Open' Chemical Biology Data. EU-OPENSCREEN has recently started, and is in the so-called 'Preparatory Phase'.

The job will require someone with good technical informatics and scientific skills connected with database design and integration, biological screening, bioinformatics and chemoinformatics, data security, and will require travel to European and U.S. collaborator labs. 

An associated EU-OPENSCREEN post within the Steinbeck group at the EBI, on Data Standards, Ontologies, etc., will also be announced shortly.

When the position is live on the EMBL recruitment site, I'll post another reminder post.

Sunday, 17 October 2010

Internships within ChEMBL


We regularly offer internships within the ChEMBL group, these are typically for between three and six months. We receive about five to ten applications per week, so only a small fraction of applications are successful. We try and match these against project ideas we have, available space, and our limited budget. Here is some advice for those wishing to apply.

Please note - working as an intern at any EMBL lab may negatively affect applications for study as a PhD student at EMBL - please check the regulations carefully if you plan to apply for a PhD.
  • Please try and be accurate about the group you are applying to, we understand that you are probably looking at many opportunities, but if you mention a completely different scientific area, PI name, or have a very vague and general application, we will be unable to consider your application further.
  • Attach a current and accurate cv (please do not feel under pressure to limit this to two pages) with your initial application. Be accurate with the description of your skills and interests.
  • We circulate the applications amongst the ChEMBL group, and then short-list candidates for a skype video call, where we will have a half-hour interview, including some technical tests.
  • The group use Apple hardware for desktop machines and you will need to be able to use UNIX (in one its many forms), command line, and standard office tools (MS Office, or equivalent). You will not be able to bring your own computer/licensed software to perform work with us.
  • We will pay you a modest stipend while you are here, but you need to fund your own travel to and from the United Kingdom where required.
  • We do not have time to reply to, or provide feedback on, every application we receive, sorry.
  • We have a broad range of project ideas, not just those listed on the page linked to below; so we welcome applications from bioinformaticians, chemoinformaticians, structural biologists, web developers, knowledge modelling and those with drug discovery backgrounds.
Details on the EMBL-EBI's internship program are found here; however, please note that there are some contradictions in the current EBI website material - specifically, we welcome applications from all nationalities.

Thursday, 14 October 2010

ChemSpider links now available in ChEMBLdb

Here at ChEMBL, we are often contacted by users who are interested in purchasing some of the compounds that we store in our databases. However, our compounds are curated directly from the literature and we do not have access to physical samples. To enable our users to find supplier information for the compounds, we have now added direct links from ChEMBL to ChemSpider. ChemSpider is a resource containing millions of chemical structures, with associated property information. This property information also includes supplier information, where available. You can connect to ChemSpider via our Compound Report Card, under "Database Links" and by clicking on the Standard InchiKey hyperlink you will be taken directly to the same compound in ChemSpider. You can also connect directly to ChEMBLdb via ChemSpider using the hyperlink found under their "Biological Data" tab.

Monday, 11 October 2010

ChEMBL_07 Downloads Available



Following last weeks announcement regarding the release of ChEMBL_07, we are now pleased to say the downloads are available on the ftpsite.

2010 New Drug Approvals - Pt. XII - Pegloticase (Krystexxa)






ATCC: M04AX02


On September 14th 2010, the FDA approved Pegloticase under the trade name Krystexxa. Pegloticase is a recombinant enzyme for the treatment of gout and can replace xanthine oxidase (XO) inhibitors for patients who do not respond to or cannot tolerate treatment with xanthine oxidase inhibitors. 

Gout is a painful affliction caused by microscopic needle-shaped crystals of sodium urate which precipitate in joints and tendons and stimulate a local inflammatory response. These attacks of inflammatory arthritis not only cause pain and stiffness of the joint, but, if left untreated for years, also damage the cartilage and surrounding tissue. Hard, non-painful deposits of crystalline uric acid known as tophi occur in the joints and sometimes the kidney. 

Gout is generally associated with obesity, hypertension, insulin resistance and hyperlipidaemia. In more than half of the cases of diagnosed gout, patients have elevated blood levels of uric acid.

Conventionally, acute gout attacks are ameliorated by administration of non-steroidal anti-inflammatory drugs (NSAIDs) and the levels of uric acid are kept low by restricting diet, and also administration of inhibitors of xanthine oxidase (UniProt: P47989, ChEMBL: 149) such as allopurinol and febuxostat. Some patients however cannot tolerate conventional xanthine oxidase inhibitors because of severe allergic reactions. It is this group of patients that pegloticase has been approved for.

Pegloticase is a recombinant uricase, an enzyme that lowers the levels of puric acid by catalyzing the oxidation of puric acid to allantoin (see image), which in turn is readily eliminated via the kidneys. The uricase enzyme exists in all mammals but is not expressed in humans (Entrez Id of the pseudo-gene: 391051) and many primates. Therefore, pegloticase reduces uric acid levels through a catabolic function that has been relatively recently 'lost' in human evolution.





Pegloticase is a modified version of the mammalian uricase and is expressed in E.coli. Each uricase subunit is conjugated to monomethoxy-polyethylene-glycol (mPEG) and the enzyme occurs as a tetramer weighing ~540 kDa.

Eight milligram of Pegloticase are administered every two weeks as a parenteral infusion. In a single-dose, dose-ranging trial, Pegloticase reduced uric acid levels in a dose dependent manner and for doses of 8mg and 12mg, uric acid levels were kept below 6mg/dL for more than 300 hours (n=4).

Krystexxa comes with a boxed warning regarding anaphylaxis and infusion reactions as in clinical trials it caused anaphylaxis in 6.5% of patients treated with Krystexxa every 2 weeks and infusion reactions in 26% of these patients.

The sequence of Peglocitase is very similar to that of pig uricase (UniProt:P16164)

>Peglocitase
TYKKNDEVEFVRTGYGKDMIKVLHIQRDGKYHSIKEVATTVQLTLSSKKDYLHGDNSDVIPTDTIKNTVNVL
AKFKGIKSIETFAVTICEHFLSSFKHVIRAQVYVEEVPWKRFEKNGVKHVHAFIYTPTGTHFCEVEQIRNGP
PVIHSGIKDLKVLKTTQSGFEGFIKDQFTTLPEVKDRCFATQVYCKWRYHQGRDVDFEATWDTVRSIVLQKF
AGPYDKGEYSPSVQKTLYDIQVLTLGQVPEIEDMEISLPNIHYLNIDMSKMGLINKEEVLLPLDNPYGKITG
TVKRKLSSRL
Pegloticase must not be given to patients suffering from glucose-6-phosphate dehydrogenase (G6PDH) deficiency as there is a risk of hemolysis and methaemoglobinemia.

Krystexxa is marketed by Savient Pharmaceuticals Inc., the full prescribing information can be found here.

Monday, 4 October 2010

DrugEBIlity - Structure-based component


Following some successful initial testing and feedback, we have opened up the Structure-based scoring component for full Open Access - please be aware that this is still be considered to be in a test phase, since the coding pixies are still tinkering away in the background. This used to be known as Strudle, which is a name we will not use externally for structure-based assessment methods - The overall name for the druggability services from the ChEMBL group at the EMBL-EBI will be known as DrugEBIlity - cool name eh? It's got EBI in there, obeys a reasonable linguistic construction (it may even be a heterograph, but I'm not sure), is an atrocious pun, and states our view that drugability has one G. Remember that there is a capital I next the the lowercase l.....

The current portal allows you to search with a sequence, with a PDB code, or to upload a structure of your own. We are still establishing a reasonable capacity and farm priorities for uploaded structures, so please be considerate of other that may wish to use the service. We will keep an eye on the error logs and improve error reporting. If you have any questions, please use the normal Chembl support email address.

If you are interested in using the DrugEBIlity web service as part of your research, you are strongly encouraged to look out on the blog for announcements on a couple of webinars we will be running, which will detail what is actually going on, some limitations with the current implementation, and also some of our experience (e.g. do not use it on homology models and expect to get something useful, unless you have been really careful in your modelling). Remember the scoring is based on the conformational state of the protein structure that is analysed, so try and look at other known protein structures to see if there is potentially an induced, or cryptic 'drugable' site. Finally, bear in mind that it is a statistical method, with some error, it is not meant to be definitive, but acts as a guide.

The intent is to provide download of both the database and also the software, but quite a lot of localization will be required, and providing this capability will depend on the level of demand from the user community.

The licensing for DrugEBIlity is under the conditions of the standard EMBL-EBI Terms of Use, and our standard Creative Commons - Attribution Share-Alike 3.0 Unported license.

Sunday, 3 October 2010

ChEMBL licensing


The data content in ChEMBL is licensed under a highly permissive Creative Commons license - specifically the "CC Attribution-ShareAlike 3.0 Unported license"

The required attribution should contain the url of the ChEMBL resource, and also the release version, e.g.:

ChEMBL data is from http://www.ebi.ac.uk/chembl - the version of ChEMBL is ChEMBL_07.

This should be visible on the entry portal for a web resource in which ChEMBL is integrated, or contained with the documentation for any further distribution.

2010 New Drug Approvals - Pt. XIII - Fingolimod (Gilenya)



ATC code: L04AA27

On September 21st, the FDA approved Fingolimod (previously known as FTY-720) for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod is marketed under the name Gilenya and is the first oral drug that can slow the progression of MS.

MS is a chronic autoimmune disorder affecting the central nervous system (CNS) and causing a broad spectrum of neurological symptoms ranging from numbness of the limbs and muscle weakness to cognitive impairment, depression, and a broad spectrum of other disorders. People suffering from MS experience inflammatory reactions which damage the myelin sheath surrounding the axons of nerve cells. The inflicted lesions impair the transmission of action potentials and ultimately perturb normal function of the CNS.

Upon administration, Fingolimod is phosphorylated by sphingosine kinase (Uniprot: Q9NRA0) to form the the active metabolite Fingolimod-phosphate - Fingolimod is therefore a prodrug. Fingolimod-phosphate binds the sphingosine 1-phosphate receptors S1PR-1, S1PR3, S1PR4 and S1PR5 (Uniprot: P21453,  Q99500, O95977, Q9H228) with high affinity and thereby blocks the capacity of leukocytes to migrate from lymph nodes into the peripheral blood. These receptors are also known as EDG receptors, and are all members of the rhodospin-like GPCR family (PFAM: PF00001), the largest single historical successful family of drug targets (GPCR SARfari: S1PR-1 (aka. EDG1)). The curative mechanism underlying Fingolimod's therapeutic effect is unknown but may involve a reduced migration of lymphocytes into the CNS.

The chemical structure of Fingolimod was derived from the natural product Myriocin (a natural product, first isolated from the fungus Isaria sinclairii), which is known as an immune suppressor and inhibitor of the sphingosine biosynthesis. Myriocin is a structural analogue of sphingosine.

The approved medication Gilenya is an oral capsule containing 0.56mg of the hydrochloride salt of Fingolimod which is equivalent to 0.5mg of Fingolimod. Dosage is 0.5mg per day - equivalent to 1.6 umol.

The peak concentration of Fingolimod in the blood is reached after 12 to 17 hours (TMAX) after oral administration and steady-state concentrations are reached after 1-2 months of daily oral administration, and are around ten-fold higher than from a single dose. Fingolimod is highly absorbed, having a bioavailability of 93%, and is also highly protein bound >99.7%, and has a high volume of distribution (Vd) of 1200L. The apparent half-life is 6 to 9 days, with a clearance of 6.3L.hr-1. Metabolisation of Fingolimod follows a main route of fatty acid-like degradation after oxidative biotransformation mainly by CYP4F2 (Uniprot: P78329).

Adverse side effects include headaches, diarrhea, reduced heart rate and atriventricular blocks, a higher risk of infections, macular edema, resipiratory effects and hepatic effects.



IUPAC: 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol


SMILES: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1

InChI: 1S/C19H33NO2/c1-2-3-4-5-6-7-8-17-9-11-18
(12-10-17)13-14-19(20,15-21)16-22/h9-12,21-22H,2
-8,13-16,20H2,1H3

Fingolimod is marketed under the name Gilenya by Novartis.

Full prescribing information can be found here.

Friday, 1 October 2010

ChEMBL_07 is now live


Continuing the pattern of short blog posts (lots of overdue paper reviews and grants to do), ChEMBL_07, containing 2,948,069 bioactivities has just been attached to the web front end. Database dumps for the ftp site are being prepared now, and will be available, once tested, next week.

ChUG - The Chembl User Group

So,we are just starting to plan the first ChUG meeting - if you are interested, get over to the ChEMBL User Group LinkedIn group.