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March 11, 2010
7:19
Hyper-panoramic pictures of the EMBL-EBI
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

The world is a really small place, as these pictures of the EBI reveal. Many thanks to the photographer Tim Nugent.
March 09, 2010
8:01
EMBL-EBI SME forum
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

The EMBL-EBI have an active support forum for SMEs, if you are interested in joining, see details here

The picture above is of a gribble - a really cute sea animal, that nonetheless strikes fear into the heart of seafarers everywhere.
March 08, 2010
3:53
Kinase inhibitor patents over time....
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

Here is a plot of the number of WO published patents that contain the words 'kinase' and 'inhibitor' published during a particular year - these were found using the excellent SIMPLE patent system. Of course this is not the same as a hand crafted, expert search of the protein kinase inhibitor patent field, but all I wanted to do here was to see the pattern over time of publication dates.

As can be seen, there is a sharp ramp-up in published patents over the period 1997-2001 - which will correspond to a filing period of 1995-2000 (patents are typically published 18 months after filing). From around 2003 onwards the total number of published patents per year have been relatively constant.
March 05, 2010
1:25
Conference: Chemical Biology 2010, Heidelberg, Sept. 22-25 2010
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

After a fantastic TACBAC 2010 conference in Hinxton, the next conference that I have a small part in organizing is the EMBO conference, Chemical Biology 2010 at EMBL Heidelberg, running from 22nd to 25th September this year. The conference will cover a broad area of approaches and methods used in Chemical Biology including molecular imaging and switching tools, computational and structural approaches, screening methods, molecular engineering, and novel synthetic methods as applied to biological questions.

The link to further details is here.
March 03, 2010
3:18
Are there too many scientists?
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

Yesterday was yet another bad, bad news day for scientists working in the pharmaceutical industry. Our best wishes to all those affected and hopefully there will be suitable and satisfying jobs out there for everyone. Clearly there are fewer jobs than there once were, and competition for work and market forces are reducing both salaries and career options.

Scientific American have recently published a thought provoking article entitled 'Does the U.S. Produce Too Many Scientists?'. Contrast and compare to the UK Government report in yesterdays post....
March 02, 2010
2:19
A Vision For UK Research?
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

The UK's Council for Science and Technology (a government appointed body with responsibility for looking at Science, Engineering and Technology (SET) issues that cut across government departments) has just released a report - A Vision for UK Research, which recommends increased public sector funding of R&D, with one of the cited reasons to maintain international competitiveness. The recommendations are thought provoking and will probably chime well with most 'career scientists'.

We are entering interesting times in the UK for both the development of science and also the science area as a career.
February 27, 2010
7:15
NIH, FDA and personalised medicine
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

Came across an interesting presentation on the internet from Francis Collins on Personalised Medicine, related to the recently announced NIH and FDA collaboration on regulatory and translational science. Lots of nice examples, and a focus on translational science. Here is the presentation.
February 21, 2010
3:08
Beta-testing new version of kinase SARfari
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

A new data load for kinase SARfari screening data has just been completed. There is a significant growth in both the number of inhibitors (28,016 vs. 17,028), and the number of assay data-points (147,478 vs. 68,861).

It is available here

Remember it is a test version only, and if you do find any problems, please mail them...

Finally, there is a funny story behind the picture, which will emerge over the next few blog posts.
February 19, 2010
6:14
Kinase Inhibitors in Clinical Development
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

We have just restarted serious activity for Clinical Development stage compounds for chembl, with the first set dusted down being the protein kinases. So, we have updated the data from the usual sources and now have (as of Feb 2010) 244 clinical stage kinase inhibitors. These break down as follows for highest reported clinical phase (however, since many of these inhibitors are for oncology applications, there is a higher fraction than typical of Phase 2 compounds.

The breakdown of targets is as follows.

If anyone with experience of kinase inhibitor development would care to cast their eyes over these data and feedback/correct errors and so forth, before we load it all into kinase SARfari, please get in touch.
February 15, 2010
10:15
2009 New Drugs - Clarification on Dysport/AbobotulinumtoxinA
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

We have had a couple of mails about the exclusion of AbobotulinumtoxinA (aka Dysport) as a new NME in some of our analyses of drugs for 2009. This is a subtle case, and our treatment of AbobotulinumtoxinA is as follows - but basically it is not an NME.

Recently the FDA required that, due to the non-interchangeability, and potential safety issues of Botulinum Toxin A products from different manufacturers, that differing non-proprietary names were required for these products, despite the fact that nominally they contain the same active ingredient (in this case a large protein therapeutic). So Botox, marketed by Allergan, now uses the non-proprietary name onabotulinumtoxinA, while for Dysport (approved during 2009) from Ipsen, uses the non-proprietary name abobotulinumtoxinA. Since they essentially just differ by manufacturer, and not by active ingredient, we have not considered Abobotulinum toxin as being a new NME approval.
February 06, 2010
13:54
Two New Posts with ChEMBL Team
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

We have recently been awarded an Innovative Medicines Initiative grant in the area of predictive toxicology - the project is called eTox. This is a very exciting project and will build an unprecedented collaborative database of rat toxicology data for a large number of clinical development candidates. It is also a chance to work in close collaboration with a network of some of the leading European academics, SMEs and pharmaceutical companies.

We have two posts available under this funding. The first is for a scientist with experience of datamining and analysis of data, preferably with good experience of bioinformatics or chemoinformatics. The second post is for an informatician to build a data repository, and then populate this with deposited curated toxicology data.

If you have any questions about the jobs, please feel free to mail us.

The deadline for applications is 14th March 2010.
5:45
2010 New Drug Approvals - Pt. III - Liraglutide (Victoza)
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

Also approved in January is Liraglutide, on January 25th, under the trade name Victoza. Liraglutide, previously known as NN2211, is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. People with this type of diabetes are often overweight, have high blood pressure and/or cholesterol and become insensitive to insulin. Type 2 diabetes is the commonest form of diabetes, and is a major health problem in 'developed' economies.

Liraglutide works by activating the GLP-1 receptor (GLP-1R), which in turn stimulates the adenylyl cyclase pathway leading to insulin release in the presence of elevated glucose concentrations. GLP-1R is a class-II GPCR (also known as secretin receptor family). Liraglutide is the second GLP-1 agonist approved for the treatment of type 2 diabetes, after Exenatide (marketed as Byetta), which reached the market in 2005. Other -glutides in development include Taspgolutide (R1583 or BIM-507) developed by Roche, and Abiglutide (a stabilized GLP-1 analogue fused to serum albumin) from GSK.

Liraglutide is an engineered form of the natural human GLP-1 peptide (one amino acid difference to the major circulating form of GLP-1, GLP-1(7-37) - an arginine replaces a lysine at position 34), an additional modification is the addition of palmitic acid attached via a glutamic acid spacer at position 26. The molecular weight of Liraglutide is 3751.2 Da. Each standard dose contains 1.8mg of Liraglutide (equivalent to 480 nmol). Dosing is as a once daily subcutaneous (s.c.) injection.

Liraglutide has a plasma half-life of ~13 hr (far longer than the ca. 2 min half life of the natural GLP-1 peptide). Slowing the fast degradation of GLP-1 is the basis of the therapeutic mechanism of the -gliptin class of DPP-IV inhibitors, e.g. Saxagliptin and Sitagliptin). The absolute bioavailability of Liraglutide, after s.c. dosing is 55%, and has high plasma protein binding > 98%. The volume of distribution Vd is 0.07L/kg, with a clearance of 1.2 L/h.

Liraglutide has a boxed warning (risk of thyroid C-cell tumours).

Victoza is marketed by Novo Nordisk and the product website is http://www.victoza.com.
5:00
2010 New Drug Approvals - Pt. I - Tocilizumab (Actemra/RoActemra)
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

The first FDA approval of this year is Tocilizumab, approved on January 8th, under the trade name Actemra. Tocilizumab is a first-in-class interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody drug, and is indicated for the treatment of rheumatoid arthritis in adults who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Rheumatoid arthritis is a chronic and debilitating, systematic inflammatory disorder, which affects principally synovial tissues.

Tocilizumab works by blocking the signalling of IL-6, an immune system soluble cytokine that is overproduced in patients with rheumatoid arthritis. Other biological therapies for RA include tumor necrosis factor-α (TNF-α) blockers (e.g, Golimumab), IL-1 blockers (e.g., Anakinra), monoclonal antibodies against B cells (e.g., Rituximab) and T cell costimulation inhibitors (e.g., Abatacept). However, all these act through binding to different target molecules. Others drugs with the same IL-6R binding mechanism as Tocilizumab are ALD518 and CNTO-136, which are currently reported to be in Phase II clinical trials.

Tocilizumab is a recombinant humanized anti-human IL-6 receptor monoclonal antibody of the immunoglobulin IgG1κ subclass. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) - mIL-6R is also known as CD126. Tocilizumab has a molecular weight of ca. 148 kDa, with a volume of distribution of ~6.4L, a linear clearance of ~12.5 mL/h and a half-life up to 13 days. The recommended starting dosage is ~4 mg/kg followed by an increase to ~8 mg/kg based on clinical response, administrated as a single intravenous drip infusion over 1 hour, every 4 weeks. Interestingly, Tocilizumab, via blocking cytokine signalling can affect expression levels of a wide variety of CYP450 drug metabolizing enzymes, leading to the potential for drug-drug interactions.

The full prescribing information for Tocilizumab can be found here.

Tocilizumab has a boxed warning (Risk of serious infections).

Each light and heavy chain of Tocilizumab consists of 214 and 448 amino acids, respectively, and the four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds.

The license holder of Tocilizumab is Genentech, Inc. and the product website is www.actemra.com.
February 02, 2010
9:55
Minor revisions to Chembl interface
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

Many thanks to the attendees on the Small Molecule Bioactivity Course at the EMBL-EBI last week. We have a big list of things to fix, a bigger list of things to think about, and despite thinking three weeks ago that we would never want to do the course again, are now looking forward to it again next year.

We have made some minor interface changes, available at [www.ebi.ac.uk]

Frr those of you waiting for the interface/database webinars, something will be announced soon...
January 30, 2010
5:35
FAQ: How do I get some advice on how to use chembl?
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

The simplest way is to contact us at chembl-help@ebi.ac.uk.
0:11
FAQ: I've done some virtual screening using chembl, can you send me some compounds?
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

We do not have physical samples of any of the compounds in chembl, so we cannot supply any samples to you. Sorry. If you want to obtain samples of chembl compounds you do have a number of options: 1) Often the underlying literature contains a synthetic route and reagents for the compounds, this greatly helps resynthesis. 2) About 5-10% of chembl compounds are reported to be available from compound vendors (for example, you could search databases such as the excellent ZINC to find available compounds). However, the turnover of stock from compound vendors is quite high, and often a significant fraction of compounds reported to be available for purchase will be out of stock when you want them.
January 26, 2010
12:05
2010 New Drug Approvals - Pt. II - Dalfampridine (Ampyra)
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data
The second NME approval this year is Dalfampridine (trade name Ampyra), approved on January 22nd. Dalfampridine is a potassium channel blocker indicated to improve walking in adults with multiple sclerosis. Multiple sclerosis is a serious chronic disease that affects the central nervous system and in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring. The therapeutic mechanism of Dalfampridine is complex, has not been fully elucidated, but it has been shown to increase conduction of action potentials in demyelinated axons through inhibition of potassium channels, probably Shaker channels. Dalfampridine is a (very) small molecule drug (Molecular Weight 94.1 g.mol-1), fully Rule-of-Five compliant and soluble in water. Dalfampridine (also known as 4-AP) has good oral bioavailability (96% bioavailable), with a volume of distribution of 2.6 L/kg and low plasma protein binding. Excretion is mainly renal (95.9% of the dose recovered in urine) and mostly as the parent drug (90.3%). Dalfampridine metabolites are 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate (a sulphated form of the previous metabolite). These metabolites have no pharmacological activity on potassium channels. The elimination half-life of Dalfampridine is 5.2-6.5 hours. The maximum recommended dosage is 10mg twice daily (equivalent to a dose of 106uM) and full prescribing information can be found here. Dalfampridine chemical structure is 4-aminopyridine, a very simple unremarkable structure.
```
NAME="Dalfampridine" TRADEMARK_NAME="Ampyra"
SMILES="n1ccc(N)cc1"
InChI="InChI=1/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7)"
InChIKey="NUKYPUAOHBNCPY-UHFFFAOYAH"
ChemDraw=Dalfampridine.cdx
```
The license holder is Acorda Therapeutics, Inc. and the product website is www.ampyra.com.
6:08
Papers for Abstraction into Chembl...
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

We would be keen to hear of key SAR publications that people would like entered into chembl (if they aren't there already). Send us the PubMed id, and we'll add it to our list, and then see whether it is in scope (and budget!) of chembldb.

If we get sufficient input of this, we'll post the list of papers.
January 24, 2010
12:09
SMR Meeting: Regenerative Medicine, Cambridge 11th March 2010
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

The SMR run arguably the best series of UK-based drug discovery meetings - they're cheap, they are on one day and they attract great speakers, and they are pharma/biotech focussed. The next is
Regenerative Medicine: A New Frontier for Therapeutic Intervention to be held on the 11th of March, at Granta Park in Great Abington, just outside of Cambridge. Further details are on the SMR website
January 19, 2010
1:19
Anyone in the Bay Area interested in a Chembl seminar in March 2010?
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

We are speaking at the Spring ACS National meeting in San Francisco (in the polypharmacology section - it will almost exclusively be new slides!). This is in the week of March 21st to 25th 2010.

If there is any interest in a seminar, database demo, or just a chat and (fine) coffee/(so-so) beer, it would be good to meet up, so mail me if you'd like to meet.
January 18, 2010
0:28
Chembldb_2 - Press Release
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

This morning, there was a press release released, marking the official release of chembl_02. More details are in the press release, but for the blog audience, the data is available in the interface, and the databases available for download on the ftp site. Work is already underway on chembl_03, with some associated minor changes to parts of the schema and additional curation of data. There is also something exciting and special in chembl_03, but more of that later.

There is approximately 20% more data in chembl_02 than chembl_01 and new content highlights include a significant expansion of Natural Product records, and unification of all compound identifiers across all EMBL-EBI records (we use ChEBI ids) all chembldb compounds should now seemlessly and quickly make their way into PubChem.

Many, many thanks to those who have told us of the errors and ambiguities you have found. We will incorporate all of these back into the database for the entire community.
For newer readers a pointer, and for older readers with poor memory, a reminder, of the chembl FAQ, and keep an eye open of the chembl-og (or even better the RSS feed) for schema walkthroughs, support and so forth.

Two pieces of staffing news for the group. Firstly, congratulations to Patricia for her success in getting selected for an EIPOD - this is for a joint collaborative project in peptide SAR between the Koehn and Overington groups. Secondly, we welcome our first PhD student - Felix Krueger, who is immersing himself in programming, databases, British life, and data.

Complementary to the required formality of the press release - some thanks! The entire Chembl team would like to take this opportunity to thank our many friends and colleagues who have helped to date, and will do so in the future. In particular, the Wellcome Trust (especially Alan and Rebecca) for their vision and funding (and Janet, Chris, Henning and Bissan for their essential roles in the grant), the senior management of EMBL, especially Iain and Janet, for their wisdom and continuous support. We'd like to acknowledge the assistance our growing network of external curators (Malcolm, Sam, Lora, and Karen), previous interns (good luck Jigisha!), and outsourcing partners (especially Jignesh and the team). Bissan and Mark at the ICR were essential in the early days of the group, and achieved so much while we were recruiting, and they remain an important part of our work and plans. We also thank and recognise the management and staff of Inpharmatica and their investors, for much of the initial development of the databases was done at that time - you know who you are!. Prof. Hopkins, as ever, you are a star ;) Most essential though has been the friendship, focus and shared purpose of our new colleagues at the EMBL-EBI - especially our new friends in the ChEBI team, as well as the INTACT, Systems, Outreach, PANDA, HSF, EBI Industry programme partners, and many other new friends and colleagues, both at Hinxton and Heidelberg. Finally, finally; we have also been doubly blessed with 1) being able to continue working with several long-term collaborators, and 2) finding new important ones since starting at the EMBL-EBI. The future looks bright, so thank you all!
January 17, 2010
1:55
New Drug Approvals - Pt. XXIV - Bepotastine Besilate (Bepreve)
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data
We're mopping up a few drug approvals from 2009 we have not yet covered yet as monographs... Approved on September 8th 2009 was Bepotastine Besilate, marketed under the trade name Bepreve. Bepotastine is a topical, selective and non-sedating histamine (H1) receptor antagonist indicated in the treatment of itching associated with allergic conjunctivitis. Through the H1 binding, Bepotastine has broad range of anti-inflammatory effects - a stabilizing effect on mast cells, inhibition of eosinophil migration and interleukin-5 (IL-5), leukotriene B4 (LTB4) and platelet activating factor (PAF) release. Bepotastine has been previously approved in Japan, under the trade name Talion, for allergic rhinitis (2000) and urticaria and skin pruritus (2002). Bepotastine is a chirally pure, synthetic small molecule drug (Molecular Weight 388.89 g.mol-1 for Bepotastine itself and 547.06 g.mol-1 for the dosed besilate salt), is Rule-of-Five compliant and is delivered as an ophthalmic solution. Bepotastine has a low protein binding of approximately 55%, is minimally metabolized by CYP450 isozymes and elimination is mainly through renal excretion (approximately 75-90% excreted unchanged in urine). The recommended dosage is one drop directly to the infected eye(s) twice a day. The prescribing information can be found here. The structure (+)-4-[[(S)-p-chloro-alpha-2-pyridylbenzyl]oxy]-1-piperidine butyric acid, with no unusual reactive features. There is a single stereocenter in the structure, and Bepotastine is dosed as the (+) enantiomer. The physicochemistry will be dominated by the Zwitterionic nature of the molecule - a molecule of nett neutral charge, but which contains compensatory charge centers - in this case the basic nitrogen of the central piperidine ring, and the carboxylic acid (on the far right of the compound figure).
```
NAME="Bepotastine"
DRUG_TARGET="MSLPNSSCLLEDKMCEGNKTTMASPQLMPLVVVLSTICLVTVGLNLLVLYAVRSERKLHT
```
```
VGNLYIVSLSVADLIVGAVVMPMNILYLLMSKWSLGRPLCLFWLSMDYVASTASIFSVFI
LCIDRYRSVQQPLRYLKYRTKTRASATILGAWFLSFLWVIPILGWNHFMQQTSVRREDKC
ETDFYDVTWFKVMTAIINFYLPTLLMLWFYAKIYKAVRQHCQHRELINRSLPSFSEIKLR
PENPKGDAKKPGKESPWEVLKRKPKDAGGGSVLKSPSQTPKEMKSPVVFSQEDDREVDKL
YCFPLDIVHMQAAAEGSSRDYVAVNRSHGQLKTDEQGLNTHGASEISEDQMLGDSQSFSR
TDSDTTTETAPGKGKLRSGSNTGLDYIKFTWKRLRSHSRQYVSGLHMNRERKAAKQLGFI
MAAFILCWIPYFIFFMVIAFCKNCCNEHLHMFTIWLGYINSTLNPLIYPLCNENFKKTFK
RILHIRS"
```
```
SMILES="Clc1ccc(cc1)C(OC2CCN(CCCC(=O)O)CC2)c3ncccc3"
InChI="InChI=1S/C21H25ClN2O3/c22-17-8-6-16(7-9-17)21(19-4-1-2-12-23-19)27-18-
10-14-24(15-11-18)13-3-5-20(25)26/h1-2,4,6-9,12,18,21H,3,5,10-11,
13-15H2,(H,25,26)"
InChIKey="YWGDOWXRIALTES-UHFFFAOYSA-N"
ChemDraw=http://www.ebi.ac.uk/chembl/downloads/Bepotastine.cdx
```
Bepreve is marketed by IstaVision and the product website is here
January 08, 2010
1:19
Isn't Nature wonderful?
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

Of course, the Nature journal is fantastic, but I was thinking of Nature, as in Mother, here. I came across this picture on the BBC news site. The original image (at an incredible 250m pixel size) is at [rapidfire.sci.gsfc.nasa.gov]

Isn't it just wonderful!

For reference, the EBI is roughly at the centre of the spiral cloud feature in the South-East corner of the UK.
January 06, 2010
2:36
Links to/from chembldb
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

If there are any cool or neat things that anyone has done with the chembldb data and is available on the web (either with an interface or as a web service) we are very happy to link to this from our pages. So if you have anything you want linked, let us know.
January 04, 2010
10:18
Chembldb schema walkthrough - 3pm GMT, 15th January 2010
» ‎ ChEMBL - Open Access Drug Discovery And Medicinal Chemistry Data

We will host another web-meeting walkthrough of the chembldb core database schema on Friday 15th January at 3pm GMT. If you are interested in joining, please email us on this link for dial-in details. We will be using the webhuddle software for the demo so it may be worth trying it out on your machine beforehand.