ChEMBL Resources

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

Wednesday, 21 December 2011

Omics and Personalised Healthcare - February 2012


We're speaking at the forthcoming EMBL Conference on Omics and Personalised Healthcare in Heidelberg, held 16th to 18th February 2012. We'll present some of our recent work on pharmacogenetic variation, and some strategies on both data-mining and some of the implications for drug discovery.

Saturday, 17 December 2011

Three ChEMBL talks at the March ACS in San Diego



A number of the ChEMBL team will be at the ACS in San Diego next March - we'll be giving a couple of talks -  one is one drug safety (jpo) one is on peptide SAR analysis and design (Patricia Bento) and the final one is on UniChem (Jon Chambers). So hopefully see you there!

We'll be spending some time in the lab of one of our close collaborators - Mike Gilson at UCSD, but we're happy to meet up with others, give talks, training, etc. as time and travel schedules permit. So if you're interested in this, get in touch.

Update: Fixed post, to reflect three accepted talks.


PAPER ID: 20839
PAPER TITLE: "Drug combinations to reduce adverse drug reactions and improve intrapatient differences in response"
DIVISION: CINF: Division of Chemical Information
SESSION: Systems Chemical Biology and Other 

PAPER ID: 22715
PAPER TITLE: "UniChem: A prototype unified chemical structure cross-referencing and identifier tracking system"
DIVISION: CINF: Division of Chemical Information
SESSION: InChI Symposium

PAPER ID: 15760
PAPER TITLE: "Comprehensive analysis of explored and available physicochemical space for alpha-amino acids"
DIVISION: ORGN: Division of Organic Chemistry
SESSION: Peptides, Proteins, and Amino Acids

Friday, 16 December 2011

Kinase SARfari ver.5.0 Released

We would like to announce the release of new version Kinase SARfari. The latest version has been updated using the chembl_12 data, which contains:

  • Bioactivity datapoints: 503041 (+15%)
  • Compounds: 54189 (+6%) 


 Various dumps of the data from Kinase and GPCR SARfari are also downloadable from the download page.

 Of course, we welcome feedback from our users!

Thursday, 15 December 2011

Spotfire DecisionSite replacement


We used to use Spotfire DecisionSite for data visualisation, and liked it a lot - we've just found out there are some pretty major changes to the licensing; and are now looking for alternatives if we can't work out a way forward. So, any suggestions for good data exploration tools, preferably with some sort of chemistry capabilities. Ideally they would run natively on Mac OsX.

Ideas in the comments please.....

Friday, 9 December 2011

Rough Breakdown of Drug Classes for 2011

Here's the equivalent view of drug approvals for 2011 so far - pretty similar picture in terms of the distribution of molecule classes - but remember this set of drug approvals, got their USANs assigned, on average about 3 to 4 years ago, so the sets are not strictly comparable, and of course, suffer from small absolute numbers....

Wednesday, 7 December 2011

Happy ChEMBLmas!!




As part of our tradition of making Xmas seasonal eCards to all our users - above is the December 2012 card. For the geeky amongst you, there may be an Easter Egg in the image file....

Conference: Advances in Protein-Protein Interaction Analysis and Modulation


Registration is now open for a really interesting EMBO Workshop on the modulation of protein-protein interactions (ppi's). We're speaking, and will present some new stuff on annotation of ChEMBL with interacting domains, and a sort of classification of these into protein-protein interfaces (see some previous blog posts for some further details on this).

The meeting is in the beautiful French harbour town of Roscoff - the traditional home of Onion Johnnies - well, I love onions, and my name is John, and I'll be there!


Tuesday, 6 December 2011

Amgen Scholars Program


Due to a lot of wasted time in the past, my lab does not host or support applications to the Amgen Scholars Program, so please do not apply to us!

Papers: MIRIAM and Identifiers.org


The NAR Database Issue is currently in full flow, and there are many excellent articles; one important one for ChEMBL is this paper from the group of our good friend Nicolas Le Novere, at the EBI. It addresses a really important problem in biological and chemical data integration through the generation of unique and stable identifiers for records in a data collection – these are MIRIAM identifiers (MIRIAM is an acronym for Minimum Information Required in the Annotation of Models Registry (http://www.ebi.ac.uk/miriam). Identifiers.org is a new service (http://identifiers.org) that is built upon the information stored in the MIRIAM Registry and which provides directly resolvable identifiers, in the form of Uniform Resource Locators (URLs). Resources such as this are essential components for ad hoc, distributed queries across disparate data sources, and a core component for semantic web development. 

A link to the free pdf of the paper is here.

ChEMBL is in identifiers.org, give it a go!

%J Nucleic Acids Research
%D 2011
%O doi:10.1093/nar/gkr1097
%T Identifiers.org and MIRIAM Registry: community resources to provide persistent identification
%A N. Juty
%A N. Le Novere
%A C. Laibe

Monday, 5 December 2011

MIPTEC 2012 and EMBO Chemical Biology 2012


A quick post to say that two of the best conferences in Europe next year are coordinating speakers and schedules for the Drug Discovery sessions to allow a really great line-up of talks and speakers, and to allow the best use of your (always too small!) travel budgets for conference attendance in these economically tough times. More later, but pencil both conferences into your diary now!

MIPTEC 2012 - September 24th to 27th 2012, Basel, Switzerland
EMBO Chemical Biology - September 26 to 29th 2012, Heidelberg, Germany.

Saturday, 3 December 2011

Cape Town


I've just spent a great week in Cape Town, at UCT, visiting the lab of Kelly Chibale; where there's lots of activity in academic drug discovery, and also at the Institute of Infectious Disease and Molecular Medicine. My first time in Africa, and it won't be my last!

Friday, 2 December 2011

3,788 Thank yous!

So a big and heart-felt three thousand, seven hundred and eighty eight 'Thank Yous' to all the benevolent donors to the EBI Movember Team - The Bioinformoustachians. It was a lot of fun, the place is a lot hairier now, and there are more smiles on faces than at the start of the month.

Mission accomplished by our International (hair)peace keeping force - The Victoria and George Crosses (respectively) are awarded to Francesco Iorio (sgt. 8th Italian light foot) and Remco Loos (cpl. 4th Dutch commando) for their epic struggle and hand-to-hand combat for first place in the fund-raising league table, and a 'mention in despatches' is presented to Nicolas Le Novére (lt. 1st French prancers) for being the 'Top Gun' amongst the faculty. The platoon is now returning home, and will soon be changing back into 'civvies' (much to the relief of their partners and family).

If any other large science data centres want to make a fight of it for Movember 2012 - bring it on, we are waiting!

PS, it's still not too late to donate (up to December 8th 2011) at http://mobro.co/ebi

Thursday, 1 December 2011

ChEMBL 12 Released

We are pleased to announce the release of ChEMBL_12. This latest version of the ChEMBL database contains:
  • 1,222,969 compound records
  • 1,077,189 distinct compounds
  • 596,122 assays
  • 5,654,847 bioactivities
  • 8,703 targets
  • 43,418 documents
  • 7 data sources
This release includes updates to the manually extracted Medicinal Chemistry literature, a number of published ADMET datasets (for metabolic enzymes and various transporters), updates to OrangeBook drug approvals and a partial update from PubChem BioAssay. ChEMBL_12 also contains a new deposited dataset of Malaria liver-stage screening data from Novartis-GNF (for more details on this dataset, please see ChEMBL-NTD website and the recent publication in Science).

Please refer to the ChEMBL_12 release notes for a more detailed description of all changes included in this release.

You can download the data from the ChEMBL ftpsite: ftp://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/latest/

Friday, 25 November 2011

Crimewatch?


UniChem - An EBI compound structure cross-referencing resource


We have faced for some time some issues with compound integration with ChEMBL - specifically the loading of compound sets into ChEMBL for cross referencing, between for example, ChEBI, PDBe compounds, etc. The ChEMBL update cycle is relatively slow with respect to some other resources, and there is inevitable thrash with compounds not being present, especially for exciting new data. Without doing something different for compound integration, we were starting to face a scenario where we had a compound table with many millions of compounds without any bioactivity data, and following this the inevitable slowdown in searching, etc.

We also had some issues facing us about curation of other people's primary data, changing compound structures, or their rendering, etc.

So, we decided to set up an external system to resolve cross-references between various databases. This is a very simple Standard InChI lookup, containing compounds from resources such as ChEMBL, ChEBI, PDBe, DrugBank, KEGG, BindingDB, PubChem, and so forth. UniChem can also handle versioning of the contained resources. We will be migrating various components of the current ChEMBL interface across to use web services on UniChem, this way, the cross links will always be fresh and correct, and we can focus on curation and optimisation of ChEMBL content. There are some other resources, like ZINC, STITCH, and ChemSpider, for example, that would be great to integrate, if we can get hold of the required data.

The easiest way for us to handle deposition into UniChem is for us to take an ftp: feed of a simple table of resource_id, standard_InChI, and standard_InChI_key.

At the moment, UniChem sits behind our firewall, but if people want to have a play, let us know.

We will write something more specific and detailed, but would welcome thoughts of whether this resolver should be externally facing, and what other resources would be good to integrate?

The image above may or may not be the UniChem logo.

Thursday, 24 November 2011

ChEMBL Widgets Update

We have made a couple of minor updates to the ChEMBL widgets, which include:
  • A new widget has been created, which displays the bioactivity results shared between a ChEMBL compound and a ChEMBL target
  • A new scaling parameter allows you to vary the size of the widget
  • A more informative message is provided when widget has no data to display
More details can be found here

Wednesday, 23 November 2011

Further Depositions to ChEMBL-NTD


We're delighted to announce the availability of three distinct new datasets on the ChEMBL-NTD portal, available for download, reuse, etc.

These are:

  • Novartis-GNF Malaria Liver Stage dataset (associated with this Science publication) (Plasmodium falciparum).
  • DNDi Human African Trypanosomiasis (HAT) dataset (Trypanosoma brucei)
  • DNDi Chagas Dataset (Trypanosoma cruzi).


Further details of the assays and compounds are to be found on the ChEMBL-NTD portal. The data will be integrated and loaded into a future version of ChEMBL, as well as the direct data download links. Once more, we thanks the depositors, DNDi and Novartis-GNF, for their benevolence and commitment to Open Science.


The associated publication for the Novartis-GNF dataset is:
%T Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery
%A S. Meister
%A D.M. Plouffe
%A K.L. Kuhen
%A G.M.C. Bonamy
%A T. Wu
%A S.W. Barnes
%A S.E. Bopp
%A R. Borboa
%A A.T. Bright
%A J. Che
%A S. Cohen
%A N.V. Dharia
%A K. Gagaring
%A M. Gettayacamin
%A P. Gordon 
%A T. Groessl 
%A N. Kato
%A M.C.S. Lee
%A C.W. McNamara
%A D.A. Fidock
%A A. Nagle
%A T-g Nam 
%A W. Richmond
%A J. Roland
%A M. Rottmann
%A B. Zhou
%A P. Froissard 
%A R.J. Glynne
%A D. Mazier 
%A J. Sattabongkot
%A P.G. Schultz
%A T. Tuntland
%A J.R. Walker 
%A Y. Zhou
%A A. Chatterjee
%A T.T. Diagana 
%A E.A. Winzeler
%J Science
%D 2011
%O DOI:10.1126/science.1211936

Interest in Links to Patents From Structures in ChEMBL


We are exploring establishing links from the ChEMBL compounds to patents. The implementation can have two basic routes....


  • Links from the interface to patents (simple and quick to do now we have UniChem).
  • Patent uri's in the database itself (more complex, and more difficult to keep up to date, but arguably more useful).


So to help our planning for next year, comments, wishes are most welcome....

Tuesday, 22 November 2011

New Drug Approvals 2011 - Pt. XXXI Asparaginase Erwinia chrysanthemi (ErwinazeTM)






ATC code: L01XX02


On November 18, the FDA approved asparaginase from Erwinia chrysanthemi for the treatment of patient with acute lymphoblastic leukemia (ALL) who have become allergic to the E. coli asparaginase that is conventionally used for the treatment of ALL patients.

ALL is a cancer of the white blood cells and can be fatal within weeks from the onset of the disease if it is left untreated. In ALL, there is an unproportional increase in the population of immature white blood cells, which crowd out functional immune cells as well as red blood cells and platelets, and in advanced stages of the disease infiltrate into tissues and organs, most frequently liver, spleen and lymph nodes. The symptoms of ALL in its initial stages are fatigue, anemia, frequent infections and fever as well as breathlessness and prolonged bleeding. ALL is caused by DNA damage and associated with exposure to radiation and cancerogenic chemicals. There are a number of typical chromosomal translocations, the most frequent in adults with ALL is the so called Philadelphia chromosome, where a translocation of chromosomes 9 and 22 results in the formation of the fusion gene bcr-abl (CHEMBL1862). Treatment of ALL is usually encompasses the three phases i) remission induction, which aims to quickly kill off 95% of the cancerous cells, ii) consolidation to further reduce the tumor burden and iii) maintenance with the aim to prevent a relapse caused by stray surviving leukemic cells.

Aspariginase is part of the remission induction regimen and used in combination with other cytostatic and cytotoxic drugs including prednisolone (CHEMBL131), dexamethasone (CHEMBL384467) , vincristin (CHEMBL303560) and daunorubicin (CHEMBL178). Asparaginase is an enzyme (EC 3.5.1.1) that catalyzes the hydrolysis of asparagine (CHEBI:17196)  to aspartic acid (CHEBI17053) as shown below. Unlike healthy body cells, leukemic cells rely on the presence of extracellular asparagine for protein metabolism and survival, hence the beneficial effect for ALL patients. Conventionally, asparaginase for he treatment of ALL is derived from the bacterium Escherichia coli (corresponds to Uniprot:P00805) but some patients (estimated 10-15%) become allergic to this enzyme. For these patients, the ortholog from the bacterium Erwinia crysanthemi (Uniprot-Id P06608) is available to replace the untolerated treatment.

Asparaginase catalyzes the hydrolysis of asparagine to aspartic acid.
Asparaginase Erwinia crysanthemi is a tetrameric enzyme composed of four identical subunits each weighing about 35kDa. The crystal structures of many asparaginase enzymes are known, including that of the closely related protein from Erwinia carotovora (PDBe:2jk0)


The recommended dosage is 25.000 International Units/m2 (International Units compare biological activity relative to an arbitrary amount of the active ingredient, square meter refers to body surface) three times a week. The route of administration is intramuscular injection.

The pharmakokinetic paramaters of Erwinaze were not determined in clinical trials, serum concentrations greater than 0.1 International Units/mL were reached by all patients within 72 hours of the third injection of aspariginase Erwinia chrysanthemi.

Side effects reported in the study include serious hypersensitivity reactions, pancreatitis, glucose intolerance, thrombosis and hemorrhage.

Asparaginase Erwinia chrysanthemi is marketed in the US by Eusa Pharma under the trade name Erwinaze. In a number of other countries, it is available under the name Erwinase.

Package information can be found here.


Monday, 21 November 2011

New Drug Approvals 2011 - Pt. XXX - Aflibercept (EyleaTM)


ATC code (partial): S01LA

On November 18th 2011, the FDA approved Aflibercept (trade name: Eylea; Research Code: AVE-0005,  also known as VEGF Trap), a recombinant fusion protein indicated for the treatment of patients with neovascular (wet) age-related macular degeneration (AMD).

AMD is an eye condition which usually occurs in older patients and affects the macula area of the retina, causing loss of vision and eventually blindness. In particular, wet AMD is characterised by an abnormal growth of new blood vessels (neovascularisation) behind the retina. This originates from an abnormal activation of angiogenesis, by the vascular endothelial growth factor-A (VEGF-A; ChEMBL: CHEMBL1783; Uniprot: P15692) and the placenta growth factor (PlGF; ChEMBL: CHEMBL1697671; Uniprot: P49763), of the vascular endothelial growth factor receptors VEGFR-1 (ChEMBL: CHEMBL1868; Uniprot: P17948) and VEGFR-2 (ChEMBL: CHEMBL279; Uniprot: P35968), two receptor tyrosine kinases present on the surface of endothelial cells. This leads to abnormal increased permeability, scarring and possibly to the loss of fine-resolution central vision. Aflibercept acts as a soluble 'decoy' receptor that binds VEGF-A and PlGF and thereby inhibits the binding and activation of the VEGFR-1 and VEGFR-2 receptors.

Aflibercept is a recombinant fusion protein that incorporates portions of extracellular domains of the human VEGFR-1 (containing Ig-like C2-type 2 domain fragment; Uniprot: P17948|151-214|) and VEGFR-2 (containing Ig-like C2-type 3 domain fragment; Uniprot: P35968|224-320|) fused to the Fc portion of human immunoglobulin G1 (IgG1). Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kDa (115 kDa with glycosylation).


>Aflibercept
SDTGRPFVEM YSEIPEIIHM TEGRELVIPC RVTSPNITVT LKKFPLDTLI PDGKRIIWDS
RKGFIISNAT YKEIGLLTCE ATVNGHLYKT NYLTHRQTNT IIDVVLSPSH GIELSVGEKL
VLNCTARTEL NVGIDFNWEY PSSKHQHKKL VNRDLKTQSG SEMKKFLSTL TIDGVTRSDQ
GLYTCAASSG LMTKKNSTFV RVHEKDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR
TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN
GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR DELTKNQVSL TCLVKGFYPS
DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH
YTQKSLSLSP G


Other therapies to treat AMD are available on the market and these include Verteporfin (ChEMBL: CHEMBL1200573; approved in 2000; trade name Visudyne), Pegaptanib sodium (ChEMBL: CHEMBL1201421; approved in 2004; trade name Macugen) and Ranibizumab (ChEMBL: CHEMBL1201825; approved on 2006; trade name Lucentis).

Aflibercept recommended dosage is 2 mg administrated by intravitreal (into the eye cavity) injection every 4 weeks for the first 12 weeks, followed by 2 mg via intravitreal injection once every 8 weeks.

Following intravitreal administration of 2 mg per eye, a fraction of the administrated dose binds to the endogenous VEGF in the eye to form the inactive Aflibercept:VEGF complex. Once absorbed into the systemic circulation, Aflibercept presents in the plasma as the free unbound Aflibercept and predominantly as the inactive Aflibercept:VEGF complex. Aflibercept has a volume of distribution (Vd) of 6 L and a terminal elimination half-life (t1/2) of 5 to 6 days after iv administration of doses of 2 to 4 mg.kg-1 of Aflibercept. Aflibercept undergoes elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis.

The full prescribing information for Eylea can be found here.

The license holder is Regeneron Pharmaceuticals, Inc. and the product website is www.eylea.com.

Friday, 18 November 2011

New Drug Approvals 2011 - Pt. XXIX (ruxolitinib phosphate) (Jakafi ™)








ATC Code: L01XE18
Wikipedia:Ruxolitinib

On November 16th 2011, the FDA approved ruxolitinib phosphate (Tradename:Jakafi™ Research Code: INCB-018424), a JAK1/JAK2 inhibitor for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

Myelofibrosis is a disorder of the bone marrow, in which the marrow is replaced by scar (fibrous) tissue. Scarring of the bone marrow reduces its ability to blood cells, and can lead to anemia, bleeding problems, and a higher risk of infections due to reduced white blood cells. It is also associated with engorgement of organs suchs as the spleen and liver. Primary myelofibrosis may develop to secondary myelofibrosis - including leukemia and lymphoma. Myelofibrosis is associated with dysregulated Janus kinases JAK1 and JAK2, and some with a somatic mutation in JAK2 (JAK2V617F) (OMIM). JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines.

JAK1 (Uniprot:P23458) and JAK2 (Uniprot:O60674) are tyrosine protein kinases and members of the Janus kinase subfamily, where all members of the family contain two tandem protein kinase domains (PFAM:PF00069), one of which is catalytically active and one believed to be inactive. JAK1 and JAK2 are 43% identical by sequence and both have the 3D structure of their kinase domain determined (see e.g. PDBe:3EYH and PDBe:3Q32 for JAK1 and JAK2 respectively). Ruxolitinib is the first approved targeted JAK inhibitor, with several others in mid to late-stage clinical development (including CYT-387, GLPG-0634, INCB-28050, ONX-0803, NS-018, pacritinib (SB-1518), AZD-1480, BMS-911543, LS-104, XL-019, TG-101348, tofacitinib (CP-690550), VX-509, R-348, WHI-P131 and oclacitinib (PF-03394197) (veterinary applications)) - note these show a broad range of selectivity against the three known JAK subtypes.
Ruxolitinib (IUPAC: (R)-3-(4-(7H-pyrrolo[2,3­ d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate; (Standard InCHI key: HFNKQEVNSGCOJV-OAHLLOKOSA-N) has a molecular weight of 404.36, an AlogP of 2.88 and complies with all components of Lipinski's rule of 5.

Ruxolitinib is administered orally as the phosphate salt as tablets and dosed according to platelet count (hence the large range of dosage forms). Each tablet contains ruxolitinib phosphate equivalent to 5 mg, 10 mg, 15 mg, 20 mg and 25 mg of ruxolitinib free base. The Tmax for Ruxolitinib is 1-2 hours post dosing, with exposure (Cmax and AUC) linear over a dose range of 5mg to 200mg. Oral absorption is in excess of 95%. The volume of distribution is 53-65 L, with plasma protein binding in excess of 97%. Ruxolitinib is predominantly metabolized by CYP3A4, with the two primary metabolites displaying weaker, but still significant pharmacological activity against their specific targets. Administration of ruxolitinib with ketoconazole, a potent CYP3A4 inhibitor, prolongs the half life of ruxolitinib from 3.7 to 6.0 hours, increases the Cmax to 33% and the AUC to 91%. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole.

The license holder for Jakafi is Incyte, and the full prescribing information can be found here.

Thursday, 17 November 2011

TACBAC 2012


A quick reminder of the TACBAC 2012 conference. Previous conferences in the series have been excellent, and so check out the website for some initial conference details.

Tuesday, 15 November 2011

Molecular Architecture of the Human ADMET System

Here is an interesting graph, it the the frequency distribution of the functional PFAM domains for the human ADMET system - more specifically, it is the distribution of domain frequencies for the single domain containing proteins (the multidomain set is being curated now). The source data comes from the PharmADME site (the graph includes the "extended set").


So just 10 distinct functional domains cover almost 75% of the domains (there are a total of 46 domains in this set). By far the most frequent domain is, unsurprisingly, the cytochrome p450 domain (PF00067).

Monday, 14 November 2011

Deadline Approaching for Current Recruitment in ChEMBL


The deadline is approaching for two posts in the ChEMBL group - one a web developer, and the other a data integration position. The posts are three year fixed term contracts. Closing dates for applications is the 27th November 2011.

Further details should be available here
If you have any questions, please feel free to contact us.

Sunday, 13 November 2011

Recommendations for a MySQL Chemical Data Cartridge?


What options are there for a MySQL Chemical Structure Cartridge ? - the constraints are that the license needs to be Open (to commercial and non-commercial users). Post away in the comments, then everyone can see the answers.

Update: for a little background on our specific interests - we wish to build a deployable and distributable version (a package or vm) with a preconfigured and loaded current ChEMBL database, capable of performing full chemical search capability. Deployment could be as a Linux style package, or as an Amazon EC2 instance. Our internal systems here at the EBI are based on Oracle, and the MDL (or whatever the current name is :) ) Direct cartridge - this configuration is sometimes beyond the reach of many budgets, and so we are interested in exploring a 'free' but useful version of ChEMBL.

Update 2: So Postgres opens up quite a few more options....

Friday, 11 November 2011

Movember Donations from Outside the United Kingdom




In responses to a question from one of the ChEMBL-og readers - I've just checked, and it is possible for non-UK residents to donate to the EBI Movember team - The Bioinformoustachians. Link for donations is above.

Tuesday, 1 November 2011

The Start of Movember - Clean Shaved and Ready To Grow!


Sorry if these posts are a little off normal topic. But the majority of the member of the EBI's team for Movember assembled yesterday for a 'before' photo. Just look at all those baby faces, look at all those chins!

Monday, 31 October 2011

Meeting: Drug Discovery Oxford 2012 - Drug discovery: a job too complex for academia or industry alone?


There is a great meeting being held in Oxford just after the Christmas break (specifically on the 5th and 6th January 2012), it's organised by the Structural Genomics Consortium, one of the longest existing advocates of Open Science in Drug Discovery.

Details of the meeting are here.

Thursday, 27 October 2011

The Bioinformoustachians!



The EBI has a team entered for the annual Movember fund raising event - this is focussed on raising money for 'male cancers' - testicular and prostate. The team is called The Bioinformoustachians!, so please consider sponsoring us over the coming month. Of course, as well as raising money for a serious cause, there will be some fun along the way as well. Watch over the next few days, as the full team signs up - we're gonna raise Loadsamoney (hopefully).

For those unfamiliar with the idea - participants are clean shaved at the start and grow a moustache throughout the month gaining sponsorship for looking stylish/silly.

The team webpage on the movember website is here. Please consider donating, and help us, together, make a difference.

New Drug Approvals 2011 - Pt. XXVIII Clobazam (OnfiTM)







ATC Code: N05BA09
Wikipedia: Clobazam

On October 24th, the FDA approved Clobazam (Tradename: OnfiTM; Research Code: RU-4723), a GABAA receptor agonist, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged two years or older.

Lenox-Gastaut syndrome is a rare and severe form of epilepsy that is typically diagnosed in childhood and often persists into adulthood. LGS accounts for 1-4% of childhood epilepsies, and it is associated with multiple types of seizures, as well as, daily periods of frequent seizures.

Clobazam decreases the frequency of the LGS seizures by potentiating GABAergic neurotransmission, trough the binding of the GABAA receptor at the benzodiazepine site.

GABAA receptor is a protein complex of five subunits (mainly α2β2γ) located in the synapses of neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter GABA, while a subset of GABAA receptor complexes also contain a single binding site for benzodiazepines, also referred to as benzodiazepine receptors (BzR). Benzodiazepines, like clobazam, bind at the interface of the α and γ subunits on the GABAA receptor. Once bound to the benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the GABA neurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedatory and anxiolytic effects.


Clobazam (IUPAC: 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione; SMILES: CN1C(=O)CC(=O)N(c2ccccc2)c3cc(Cl)ccc13; PubChem: 2789; Chemspider: 2687; ChEMBLID: CHEMBL70418; Standard InChI Key: CXOXHMZGEKVPMT-UHFFFAOYSA-N) has a molecular weight of 300.7 Da, two hydrogen bond acceptors, no hydrogen bond donors, and has an ALogP of 2.74. Clobazam is a benzodiazepine derivative, a large and well established class of pharmacologically active compounds. So far, it is the only marketed 1,5-benzodiazenpine, being prefered over the 1,4-benzodiazepines already in the market: clonazepam and nitrazepam.

Clobazam is available as oral tablets of 5, 10 and 20mg, and the recommend daily dose is twice the amount of the tablets according to body weight. It has an apparent volume of distribution of 100L at steady state, and its relative bioavailability compared to an oral solution is 100%. The major metabolite of Clobazam is N-desmethylclobazam, which has about 1/5 of the activity of clobazam. Both compounds bind to human plasma proteins (80-90% and 70% respectively). The estimated mean elimination half-life (t1/2) is approximately 36-42 hr for clobazam and 71-82 hr for the active metabolite.

Clobazam is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. In vitro metabolism studies demonstrate that clobazam and its active metabolite induce CYP3A4 activity in a concentration-dependent manner. N-desmethylclobazam is extensively metabolised by the polymorphic CYP2C19, therefore, dosage in patients who are known CYP2C19 poor metabolisers may need to be adjusted. For further drug-drug interactions please refer to the full prescribing information.

Clobazam has been granted an orphan drug designation because it is intended to treat a condition that affects fewer than 200,000 people.

The license holder for OnfiTM is Lundbeck, and the full prescribing information can be found here.

Although clobazam has just been approved in the United States, it has been marketed outside of the US for several years under various brand names, including Frisium® and Urbanyl®, both licensed by Sanofi-Aventis. A full list of brand names can be found here.

Wednesday, 26 October 2011

New Drug Approvals 2011 - Pt. XXVII Deferiprone (FerriproxTM)




 
ATC code V03AC02 
Wikipedia Deferiprone

On October 14th, 2011 FDA announced the approval of Deferiprone (trade name: FerriproxTM) for the treatment of iron overload which is potentially fatal in patients with thalassemia. Deferiprone is an oral iron chelating agent, binding excess iron in the blood and thus making it available to excretion from the body. Thalassaemia is a inherited (mostly autosomal recessive) blood disease that can lead to anemia by causing the formation of abnormal hemoglobin molecules not able to properly bind and release oxygen. Thalassaemia (OMIM: 141800 (α-) / 141900 (β-)) is sub-classified according to which of the subunits of the hetero-tetrameric (2α/2β, UniProt: P69905 / P68871) hemoglobin is affected, contrary to sickle-cell anaemia (OMIM: 603903) which results exclusively from a specific mutation in the β subunit. The primary treatment of thalassaemia major, the severe form of β-thalassaemia, requires frequent blood transfusions to establish stable levels of functional hemoglobin but results in high levels of iron accumulating and impairing organ function. Thus, the secondary treatment aims on reducing the toxic iron levels by binding excess iron utilizing an iron chelating agent such as Deferoxamine (ChEMBL ID: CHEMBL556) requiring parenteral administration; Deferiprone has the desirable property of being orally available.

Deferiprone (3-hydroxy-1,2-dimethylpyridin-4(1H)-one, canonical SMILES: CN1C=CC(=O)C(=C1C)O, Standard InChI: InChI=1S/C7H9NO2/c1-5-7(10)6(9)3-4-8(5)2/h3-4,10H,1-2H3 , ChEMBL ID: CHEMBL556, CAS number: 30652-11-0, PubChem: CID 2972, ChemSpider: 2866) is a very simple synthetic small molecule with molecular weight of 139.152 Da, it has no rotatable bonds, two hydrogen bond acceptors, one hydrogen bond donor, ALogP of -0.14 and is thus fully rule-of-five compliant. 

Ferriprox is dosed as 500 mg tablets and administred orally three times daily in doses of 25 mg/kg to 33 mg/kg body weight (rounded to the nearest half-tablet), resulting in a daily molar dose of ~38-50 mmol for a 70 kg individual. Common adverse reactions include chromaturia, nausea, vomiting and abdominal pain, among others. Ferriprox is not suitable for pregnant or nursing women. Ferriprox reaches a maximum concentration (Cmax) of 20 mcg/mL, has an elimination half life (t1/2) of 1.9 hours and is excreted renally. The volume of distribution is 1.6 L/kg and 1 L/kg in thalassaemia patients and healthy subjects, respectively. Peak serum concentrations are reached 2 to 4 hours after administration.

Ferriprox has been issued a boxed warning for its potential to cause agranulocytosis/neutropenia, hematological disorders characterized by abnormally low numbers of white blood cells potentially leading to serious infections and death. 

Ferriprox is marketed and has been developed by Apotex

The full prescribing information can be found here. Prior to its approval in North America, Ferriprox has been approved and available in Europe and Asia for several years - approval in North America had been delayed considerably by safety concerns brought forward by a clinical researcher formerly involved in the clinical studies.

Tuesday, 25 October 2011

Recruitment - Two positions in ChEMBL team now available



We have two posts available in the ChEMBL group - one a web developer, and the other a data integration post. The positions are both for three years and will be EMBL staff contracts. Closing dates for applications is the 27th November 2011.

Further details should be available here (the links are quite fragile I'm afraid, so sorry if they do not keep working for long)




If you have any questions, please feel free to contact us.

Monday, 24 October 2011

PhD studentship at the Institute of Cancer Research


From the lab of one of our collaborators comes the following......

Details of forthcoming PhD studentships at The Institute of Cancer Research ICR are now on-line; There are 12 studentships across a range of different disciplines including Biology, Chemistry, Informatics and Medical Physics. The deadline for applications is 1st December 2011.

There is a specific studentship of likely interest to ChEMBL-og readers - Identifying novel targets and target combinations for cancer using in-silico chemical biology, within the Computational Biology and Chemogenomics Team of the ICR.


This is a computational biology/lab biology PhD jointly between Dr. Bissan Al-Lazikani and Prof. Paul Workman. The project is an exciting multi-disciplnary project that will utilise bioinformatics and chemogenomics techniques, protein interaction network modelling as well as laboratory biology to identify novel drug intervention targets (and compounds) for use in combination therapies with best-in-class HSP90 inhibitors. The first two years of the project will be primarily computational (with an opportunity to do some basic Mass. Spec. proteomics work in the laboratory) and focus on multi-omics data mining, network modelling chemogenomic and druggability analysis. Discoveries made though the first two years will then be validated in the laboratory utilising RNA interference, cellular drug screening and other molecular and cellular biology techniques. The project benefits for a collaboration with Dr. Paul Huang and Dr. Julio Saez-Rodriguez (of the EMBL-EBI) who bring network proteomics and network modelling expertise.


Full details of the project can be found here.


The PhD is a four year project funded through the MRC studentship program. Please check eligibility criteria before applying.

Want to help shape the future of ChEMBL?


We are planning to hold two half-day (fun) workshops in mid February next year (i.e. the week of February 13th 2012). Aimed at medicinal chemists and molecular modellers - the idea is to develop easy to use workflows for several key tasks that drug discoverers often want to do, and could do more efficiently with the ChEMBL data.

The workshops will be on campus here at Hinxton, and will start around 10.30am and finish around 3pm (lunch, coffee and cakes will be provided); the focus will be on....


  • Day 1 - Use of ChEMBL in lead optimisation
  • Day 2 - Use of ChEMBL for library design/compound purchase


If you are interested in helping, please mail us, and tell us what session you'd most like to attend. Space will be limited to around 8 attendees.

Friday, 21 October 2011

Why Movember is Important


'Excluding skin cancer, prostate cancer is the most commonly diagnosed cancer among men in the US and the second most common cause of cancer death among men. It is estimated that about 1 in 6 men in the US will be diagnosed with prostate cancer during their lifetime and 1 in 36 will die from this disease.'


Quote from Cancer Facts & Figures 2010. American Cancer Society