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

Sunday, 20 December 2009

Conference: MGMS Cutting Edge Approaches to Drug Discovery, March 2010


Another good one-day conference next year is the Molecular Graphics and Modelling Society (MGMS) meeting 'Cutting Edge Approaches to Drug Design - 2010' which is held at SOAS on Friday the 12th of March 2010. SOAS is right in the center of London, near to Russell Square tube station, there is loads of cool stuff to do nearby (as well as the talks, of course).

Friday, 18 December 2009

Conference: EMBO/EMBL Chemical Biology 2010


A heads up for a conference on Chemical Biology in September 2010 at EMBL headquarters in the charming German city of Heidelberg. The dates are 22-25 September, and more details will shortly be available on the www.embl.de/conferences website. However, much like TACBAC 2010, we anticipate substantial interest in the conference, so I thought I'd highlight the conference early for you so you could mark your brand new 2010 diaries.

Happy Holidays from all in the ChEMBL team!




It is snowing here in the south-east corner of the United Kingdom, and the traditional winter holidays are almost here, so here is our card, from us, to you, with all our best wishes and thoughts.

Thursday, 17 December 2009

Postdoctoral Position in Computational Chemical Biology/Chemogenomics, ICR


There is a position available that may be of interest to readers of the blog, it is in the lab of one of our close collaborators; the position is a Post-doctoral Training Fellow - Section of Cancer Therapeutics of the Institute of Cancer Research, based in Sutton, Surrey. find here the link to the advert, the deadline for applications in 15th January 2010.

The internet is a wierd place, especially at Christmas, look at that picture - a steak cake (alliterative rhyming food names, cool).

Monday, 7 December 2009

New FDA Approved NMEs of 2009 (so far)



A brief note, really just a picture of a table of the New Molecular Entities of 2009 - there will undoubtedly be a few more approved this year, but this is the story so far.

24 New NMEs; of which 5 are biologicals, 5 are Natural Product derived, 14 are synthetic small molecules. 12 of the drugs have a black box warning at launch. 13 of the NMEs are orally dosed, and 13 pass the Rule of Five.

Now back to thinking about EU grants.....

New Drug Approvals - Pt. XXIII - Ecallantide (Kalbitor)





The first approval of the last month of 2009 is Ecallantide (trade name Kalbitor), approved on December 1st. Ecallantide, previously known by the research code DX-88, is a human plasma kallikrein (P03952) inhibitor indicated for treatment of acute attacks of Hereditary Angioedema (HAE) in patients 16 years of age or older. HAE is a rare genetic disorder, giving the carrier low levels of C1-esterase inhibitor (C1-INH) activity and inherited as an autosomal dominant trait.

C1-INH is the major endogenous inhibitor of plasma kallikrein, and functions to regulate activation of the complement system and also the intrinsic coagulation (or 'contact system' pathway). One critical aspect of this system is the conversion of High Molecular Weight kininogen (HMWk) to the nona-peptide bradykinin by the trypsin-like serine protease - plasma kallikrein. During HAE attacks, disregulated activity of plasma kallikrein result in excessive bradykinin generation; bradykinin is a potent vasodilator, and this activity is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation and pain.

Ecallantide has a block box warning (risk of anaphylaxis).

Ecallantide is a potent, selective, reversible inhibitor of plasma kallikrein (Ki of 25pM), which binds to the active site and blocks further access of substrates. Ecallantide is the first subcutaneous treatment approved in the U.S.A. The other available treatment involves the intravenous administration of C1-INH itself. Ecallantide is a polypeptide of 60 aminoacids (Molecular Weight 7054 Da), with a volume of distribution of 26.4L, a plasma clearance of 153 mL/min and an elimination half-life of ~2 hours. The recommended dose is 30 mg, administered subcutaneously as three 10 mg doses (each in 1 mL) injections (the typical dosage is therefore 0.43umol).

Ecallantide is a synthetic peptide, related to region 20-79 of the natural gene Tissue Factor Pathway Inhibitor (P10646), and contain 3 internal disulphide bonds.

Ecallantide sequence: EAMHSFCAFKADDGPCRAAHPRWFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRD
Ecallanetide target sequence: GCLTQLYENAFFRGGDVASMYTPNAQYCQMRCTFHPRCLLF 
SFLPASSINDMEKRFGCFLKDSVTGTLPKVHRTGAVSGHSLKQCGHQISACHRDIYKGVD 
MRGVNFNVSKVSSVEECQKRCTNNIRCQFFSYATQTFHKAEYRNNCLLKYSPGGTPTAIK 
VLSNVESGFSLKPCALSEIGCHMNIFQHLAFSDVDVARVLTPDAFVCRTICTYHPNCLFF 
TFYTNVWKIESQRNVCLLKTSESGTPSSSTPQENTISGYSLLTCKRTLPEPCHSKIYPGV 
DFGGEELNVTFVKGVNVCQETCTKMIRCQFFTYSLLPEDCKEEKCKCFLRLSMDGSPTRI 
AYGTQGSSGYSLRLCNTGDNSVCTTKTSTRIVGGTNSSWGEWPWQVSLQVKLTAQRHLCG 
GSLIGHQWVLTAAHCFDGLPLQDVWRIYSGILNLSDITKDTPFSQIKEIIIHQNYKVSEG 
NHDIALIKLQAPLNYTEFQKPICLPSKGDTSTIYTNCWVTGWGFSKEKGEIQNILQKVNI 
PLVTNEECQKRYQDYKITQRMVCAGYKEGGKDACKGDSGGPLVCKHNGMWRLVGITSWGE 
GCARREQPGVYTKVAEYMDWILEKTQSSDGKAQMQSPA 
The full prescribing information can be found here.

The license holder is Dyax Corp. and the product website is www.kalbitor.com.

Monday, 30 November 2009

For those in the Cambridge UK area....


We have Jean-Louis Reymond visiting us on the morning of Friday the 4th of December, he is going to give a seminar on his group's GDB databases (see previous blog posts, I think this is a very exciting area of science at the moment). If you are interested in coming, please mail me for details and to arrange access to campus.

Again xkcd is the source for the cartoon.

Friday, 27 November 2009

New Drug Approvals - Pt. XXII - Romidepsin (Istodax)

Approved on November 5th 2009 was Romidepsin (trade name Istodax). Romidepsin, previously known by the research codes FK-228, FR-901228 and NSC-630176, is a histone deacetylase (HDAC) inhibitor indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. CTCL is a slow-growing cancer of infection-fighting white blood cells called T-lymphocytes. Romidepsin binds directly to the HDAC active site blocking substrate access. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. Romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of cancer cells. Romidepsin is the fourth drug to be approved for CTCL, after Vorinostat (trade name Zolinza), Bexarotene (trade name Targretin) and Denileukin Difitox (trade name Ontak). Vorinostat is a small-molecule drug which also inhibits HDACs, whereas Bexarotene is a small-molecule retinoid selective for retinoid X receptors and Denileukin Difitox is an engineered protein combining interleukin-2 and diphtheria toxin, which binds to interleukin-2 receptors and introduce the diphtheria toxin into cells that express those receptors, killing the cells. Romidepsin is a Natural Product drug discovered from a fermentation broth of the bacteria Chromobacterium violaceum. It is a cyclic peptide with a molecular weight of 540.71 g.mol-1. It is highly protein bound in plasma (92% to 94%), with alpha1-acid-glycoprotein being the principal binding protein. Romidepsin undergoes extensive metabolism primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6 and CYP2C19. It has a terminal half-life of ~3 hours. Among one of the potential adverse events is the propensity for the compound to increase QT interval. The recommended dose of Romidepsin is 14 mg.m-2 administrated intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. The full prescribing information can be found here. Romidepsin's chemical structure is (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone. It is a cyclic depsipeptide (peptide in which one or more amide bonds are replaced by ester bonds) with four component amino acids and a beta-hydroxyamide moiety (an amide and an hydroxy functional groups separated by two carbons atoms), which collectively form a 16-membered lactone with a disulfide bridge. The disulfide bond is reduced in the cellular environment, releasing the free thiol analogue as the active species.
<NAME="Romidepsin">
<SMILES="CC=C1C(=O)NC(C(=O)OC2CC(=O)NC(C(=O)NC(CSSCCC=C2)C(=O)N1)C(C)C)C(C)C">
<InChI="InChI=1S/C24H36N4O6S2/c1-6-16-21(30)28-20(14(4)5)24(33)34-15-9-7-8-10-35-
36-12-17(22(31)25-16)26-23(32)19(13(2)3)27-18(29)11-15/h6-7,9,13-15,17,19-20H,8,10-
12H2,1-5H3,(H,25,31)(H,26,32)(H,27,29)(H,28,30)/b9-7+,16-6-/t15-,17-,19-,20+/m1/s1">
<InChIKey="OHRURASPPZQGQM-GCCNXGTGSA-N">
<ChemDraw=Romidepsin.cdx>
The manufacturer of Romidepsin is Gloucester Pharmaceuticals, Inc. and the product website is www.istodax.com.

Thursday, 26 November 2009

FAQ: Is there a license agreement I need to sign for chembl?

There is no need to sign a license agreement for any of the chembl data or applications. Nor is there the requirement for any payment. The data/software is covered by a creative commons licence - Creative Commons Attribution-Share Alike 3.0 Unported License. If you have any detailed questions about licensing please get in contact with us.

Wednesday, 25 November 2009

Conference: TACBAC 2010 - an update


A brief update of the forthcoming TACBAC 2010 conference. The schedule is now online and it looks very, very good (conflict of interest - I am motivated to say that). But really it does! Have a look for yourself if you don't believe me.

TACBAC 2010 schedule

The picture above is the top hit for "TACBAC" in google images. TACtical BACon.

FAQ: Where can I download StARlite?

Bad news and Good news: You cannot download StARlite. StARlite was a registered trademark for a database developed and marketed by Inpharmatica Ltd. Some of the databases and intellectual property of Inpharmatica Ltd. were licensed to the EMBL-EBI. What used to be known as StARlite is now part of chembl. chembl downloads accessible from here.

Tuesday, 24 November 2009

Chembldb schema web meeting - 3pm GMT, 27th November 2009


Following unanticipated child illness last week, we will have a web-meeting walkthrough of the chembldb core schema on Friday 27th November at 3pm GMT. The excellent webhuddle will be used, so if you are interested it may be worth checking this out, setting up an account, checking it works on your machine, in advance of the meeting. Mail us if you want links to the phone number and webhuddle link.

We are aware that the 27th is over the forthcoming Thanksgiving weekend for our friends located in the United States of America, but we will do a further web-meeting the following week, for those unable to make it on the 27th.

Please, please, please use the above link, it is just too complex (for me) to manage emails with all sorts of titles, content and so forth! Also, it causes confusion (for me) if you forward the access details, and then I get messages, phone calls, smoke signals, etc. about the meeting if we need to change things.

I have just joined Google wave, and have a few invitations left if anyone is interested in getting one.

Friday, 20 November 2009

Chembldb interface question



We have received a couple of questions about the 'privacy' of chemical structure searching of our chembldb interface. The root of these questions seems to be 'Is it safe for me to search with a proprietary structure?'. There are probably two components to this - privacy over the route to our servers, and the privacy of the query once it gets on to our site. Basically, we're not interested in what you are searching for, we don't store the queries at all, and have no desire to disclose this sort of data to anyone; however, there are a number of things we could do in the short-term to address some potential corporate/IP concerns.

What should be top priority for chembldb interface chemical searching functionality?
It's perfect, leave it alone!
Add tls encryption (previously generally refered to as https/ssl)
Distribute code for the interface and make an install package
  
pollcode.com free polls

We would also welcome contact/discussion to help us develop our longer term 'privacy' strategy for chembldb.

The image is from the excellent xkcd.....

EBI Interfaces blog



There are only two issues with website implementation - 'interface' and 'content'. We have a project here at the EMBL-EBI connected with interface and UI principles, and they have a blog, here is a link to that blog.

Wednesday, 18 November 2009

ChEMBL Molecular Interactions



ChEMBL small molecule-protein interactions are now available in PSI-MI TAB and XML formats, thanks to the
Proteomics Services group. This dataset includes ChEMBL interactions identified via binding assays with IC50/Ki/EC50/Kd values below 10uM - just under 500,000 interactions in total (with negative/weaker interactions also included in the XML export).

The data can be accessed via the
PSICQUIC project (Proteomics Standards Initiative Common QUery InterfaCe), which provides programmatic access to a wide range of molecular interaction databases via SOAP and REST web services. For example, this URL retrieves all ChEMBL interactions relating to imatinib (Gleevec).

Mail us
if you need more info.

Monday, 16 November 2009

ようこそ、ケンブルへ! - Welcome to 剣舞瑠 ! -



The following is written in Japanese....
ケンブルチーム(ChEMBL Team)は、欧州バイオインフォマティクス研究所(EMBL-EBI)にあり、創薬研究に有用な化合物やターゲット情報を提供するデータベースを開発しています。

ChEMBLdbは、創薬研究に有用な医薬品化合物の情報を提供するデータベースです。現在、約50万個の化合物情報、約190万件の活性情報及びそれらのターゲット情報が登録されています。ユーザーは、生物活性化合物の情報を部分構造検索や類似性検索で調査したり、また、ターゲットのアミノ酸配列からBLAST検索でアッセイ情報を収集することができます。

ケンブルチームでは、キナーゼに特化したカイネースサファリ(Kinase SARfari)のサービスも開始しました。

日本語でのご質問、ご要望はkaz(at)ebi.ac.ukまでどうぞ。チームメンバー一同、皆さんのご利用をお待ちしています!

Sunday, 15 November 2009

Conference: Rocky '09





My kids all think I have a really easy life - international travel, 'holidays' all around the world, and they regularly come out with the line 'hard day at the ice-cream factory?' when I say how busy or stressed at work I am. The latest conference we are presenting at does not help, but why oh why do they never hold the conferences I am invited to in somewhere like the Faroe Islands, where the cod fishing is good.

Anyway, we are speaking at Rocky '09, an ISCB conference held in Aspen, CO from 10th to 12th December. It looks a really, really interesting conference. Here is a link to the schedule.

Tuesday, 10 November 2009

New Drug Approvals - Pt. XXI - Ofatumumab (Arzerra)




The latest approval this month, on October 26th, was Ofatumumab (trade name Arzerra). Ofatumumab is a CD20-directed cytolytic monoclonal antibody indicated for the treatment of patients with refractory chronic lymphocytic leukemia (CLL) who have inadequately responded to both Fludarabine and Alemtuzumab. CLL is characterized by an abnormal proliferation of lymphocytes so-called B-cells. B-cells originate in the bone marrow and are involved in fighting infection. In CLL, the DNA of a B-cell is damaged and so it can not produce antibodies in order to fight infection. Moreover, they grow out of control and accumulate in the bone marrow and blood.

Ofatumumab is an IgG1k human monoclonal antibody which binds specifically to both the small and large extracellular loops of CD20. CD20 is a non-glycosylated phosphoprotein expressed on normal B lymphocytes and on B-cell CLL. Since it is not shed from the cell surface, it allows for antibody binding, and when so, it sends a signal across the membrane to control growth and trigger death of certain tumor cells. The Fab domain of Ofatumumab binds to the CD20 molecule, whereas the Fc domain mediates immune effector functions that result in B-cell lysis.
Ofatumumab has a molecular weight of ca. 149 kDa. The dosing is typically 12 doses administered as an initial 300mg dose, followed 1 week later by a 2,000mg dose weekly for 7 doses, followed 4 weeks later by a further 2,000 mg every 4 weeks for 4 doses (a 2g dose is equivalent to ca. 134umol). It has a volume of distribution ranging from 1.7 L to 5.1 L and its elimination occurs through both a target-independent route and a B-cell mediated route. Ofatumumab clearance is approximately 0.01 L/hr and mean half-life is ca. 14 days. The recommended dosage and full prescribing information can be found here.

<CHEMBL_DRUG>
<DRUG_NAME="Ofatumumab" TRADEMARK_NAME="Arzerra">
<DRUG_TARGET UNIPROT="P11836" TARGET_NAME="CD20">
MTTPRNSVNGTFPAEPMKGPIAMQSGPKPLFRRMSSLVGPTQSFFMRESKTLGAVQIMNG
LFHIALGGLLMIPAGIYAPICVTVWYPLWGGIMYIISGSLLAATEKNSRKCLVKGKMIMN
SLSLFAAISGMILSIMDILNIKISHFLKMESLNFIRAHTPYINIYNCEPANPSEKNSPST
QYCYSIQSLFLGILSVMLIFAFFQELVIAGIVENEWKRTCSRPKSNIVLLSAEEKKEQTI
EIKEEVVGLTETSSQPKNEEDIEIIPIQEEEEEETETNFPEPPQDQESSPIENDSSP
</DRUG_TARGET>
</DRUG>
</CHEMBL_DRUG>
The license holder is GlaxoSmithKline and the product website is www.arzerra.com.

Web seminar on chembldb schema


We will have a web-meeting walkthrough of the chembldb core schema on Friday 20th November at 3pm GMT. The excellent webhuddle will be used, so if you are interested it may be worth checking this out, setting up an account, checking it works on your machine, in advance of the meeting. Mail us if you want links to the phone number and webhuddle link.

Recruitment: Data Integration Position for ChEMBL


Details for a new position within ChEMBL, available for a three year period, are now listed on the EMBL recruitment website.

The ChEMBL job is (W/09/087/EBI). Closing date is the 30th November 2009.

The image above is a visualisation of the continental United States of America, visualised by distance to the nearest McDonald's restaurant. Further details and attribution are in the image itself.

New Drug Approvals - Pt. XX - Pazopanib (Votrient)



Another drug onto the market this month is Pazopanib, marketed as Votrient, which was approved on October 19th. Pazopanib Hydrochloride (previously known as GW-786034-B) is the sixth drug to be approved for kidney cancer, after Sorafenib (trade name Nexavar), Sunitinib (trade name Sutent), Temsirolimus (trade name Torisel), Everolimus (trade name Afinitor) and Bevacizumab (trade name Avastin). Sorafenib and Sunitinib are both orally dosed small molecule inhibitors of tyrosine protein kinases, which interfere with tumor growth by inhibiting angiogenesis as well as tumor cell proliferation; Temsirolimus and Everolimus are specific inhibitors of mTOR (mammalian target of rapamycin), a serine-threonine kinase, which interfere with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells; Bevacizumab is a monoclonal antibody that recognizes and blocks VEGF, which is a chemical signal that stimulates angiogenesis. Pazopanib is a small-molecule drug (Molecular Weight is 437.5 g.mol-1 for Pazopanib itself and 474.0 g.mol-1 for the HCl salt), fully Rule-of-Five compliant, lipophilic and practically insoluble in aqueous media. It is orally absorbed, has a high plasma protein binding of >99% and is metabolized by CYP3A4 (and therefore has many drug-drug interactions with substrates, inhibitors and inducers of CYP3A4) with minor contribution from CYP1A2 and CYP2C8. Pazopanib has a mean half-life of 30.9 hours and elimination is primarily through feces (>96% of dose). The recommended dosage is 800mg once daily (equivalent to ca 1.8 mmol). Among one of the potential adverse events is the propensity for the compound to increase QT interval. Full prescribing information can be found here. Pazopanib has a boxed warning. The structure 5-[[4-[(2,3-dimethyl-2H-indazol-6­-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide. Pazopanib is largely planar and and mimics the adenine ring of the enzyme cofactor ATP. Of additional note is the presence of an aryl-sulphonamide (in the bottom left of the image) - these are often weakly acidic.
<NAME="Pazopanib">
<SMILES="O=S(=O)(N)c1c(ccc(c1)Nc2nccc(n2)N(c4ccc3c(nn(c3C)C)c4)C)C">
<InChI="InChI=1/C21H23N7O2S.ClH/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16;/h5-12H,1​-4H3,(H2,22,29,30)(H,23,24,25);1H" >
<InChIKey="MQHIQUBXFFAOMK-UHFFFAOYAU">
<ChemDraw=Pazopanib.cdx>
The manufacturer of Pazopanib is GlaxoSmithKline and the product website is www.votrient.com.

Sunday, 8 November 2009

Guidance for people interested in developing against the chembldb schema/downloads


The chembldb SAR data and an initial front end is now available (see earlier posts), over the next few months we will be making quite a few changes to the data, the database, and so forth. Most excitingly, there is a large bolus of 'new' data to add. Most of the changes we make will be evolutionary, but there will be a few major things as well.

With this in mind, please mail us if you are building any systems that rely on the data, this way we can tell you in advance specifically what we are intending to do, and secondly, you could request features, cross-references, and so forth that could make your life so much easier.

I can't remember where I found the image above, but it is a little bit funny, for those of us that travel in economy/coach.

Friday, 30 October 2009

Kinase SARfari Update

The Kinase SARfari interface has been updated and is now using the JME Molecular Editor for compound drawing and editing. JME is an easy to use fast loading applet, for more information visit: http://www.molinspiration.com/jme/

ChEMBL notifications, updates, social media and news.


When I started work, if you wanted to tell someone something, you wrote a handwritten note, posted it internally to a typing pool, told them how many copies you wanted, and a few days later things would turn up in the internal post. To distribute things further, you had to then fill envelopes, lick stamps and then post them. (For the youth reading this, Google any of the unfamiliar words/phrases). It was incredible that anything got done at all (penicillin, the transistor, gps, etc it really is.
We live in different times, and as a group we communicate in three general ways to the world.

  • The ChEMBL-og chembl.blogspot.com - this blog! Mostly news of broad interest, some ephemera, some recruitment, and some analyses of data, new drug approval news, interesting papers, conferences, book and hotel reviews for scientists, etc.
  • The Group homepage at www.ebi.ac.uk/chembl - links to the online resources (currently kinase sarfari and chembldb are live).
  • The ChEMBL twitter feed www.twitter.com/chembl - mirrors most posts from the blog, occasional 'just had a really tasty burger', 'need a quarter inch Whitworth spanner', you have been warned.
  • The chembl-announce mailing list listserver.ebi.ac.uk/mailman/listinfo/chembl-announce - formal news about data/software releases.

    The picture above is from b3ta (Often NSFW) - the United Kingdom have a major (physical) postal strike in the UK at the moment.

Wednesday, 28 October 2009

Chembl database web interface and data downloads are now live


The initial web front-end to the ChEMBL SAR data is now available on the EMBL-EBI website, as are data downloads in MySQL and a variety of Oracle format downloads.

The web interface is at http://www.ebi.ac.uk/chembldb/index.php

The database downloads are at ftp://ftp.ebi.ac.uk/pub/databases/chembl/chembl_01/

We'll add some front-end documentation in the near future, and also restart the schema walkthrough web meetings, so if you are interested in these, please sign up to the chembl-announce mailing list, or configure an RSS feed on the blog.

The picture above is the unbelievable 'King of Herrings', a charmingly named and only occasionally encountered deep sea oarfish, it is the world's longest bony fish you know...

Recruitment: Data Integration for ChEMBL


We have a new position available within the ChEMBL group from January 2010 onwards - the role is for someone to do data integration, analysis, and work-flow prototyping for chemogenomics/bioassay data. The post should be advertised on the EMBL recruitment website soon, there are also several other excellent jobs listed at EMBL-EBI.

Conference: TACBAC 2010


Registration for TACBAC 2010 is now open - TACBAC stands for Therapeutic Applications of Computational Biology and Chemistry. Details on the conference can be found here

Deadline for Bursaries for Small Molecule Bioactivity Course is Approaching




The deadline for application for bursaries for the small molecule bioactivity course at the EMBL-EBI is approaching - Friday November 6th. If you wish to attend for free (or at a really discounted rate) please consider applying now. We are starting to assemble the material for the course now, and have secured some truly outstanding external speakers - it should be good!

Sunday, 25 October 2009

SMR Award Meeting: Recent Disclosures of Clinical Candidates - December 10th, London.


There is, what looks like, an excellent meeting in London, full details are on the SMR website. I hope I feel better by then.


SMR Award Meeting: Recent Disclosures of Clinical Candidates
10th December 2009
 
National Heart & Lung Institute, Kensington, London
Programme:

09.30
Registration and coffee
10.00
SMR Award lecture: The Discovery and development of Januvia, Dr. Ann Weber, Merck
(Introduction by - Rob Williams, 
Cancer Research UK)

Session 1 - Chair: Mark Searcy, University of East Anglia
11.00   
Chris Murray, Astex
From fragment to clinic - the discovery of the hsp90 inhibitor, AT13387.
11.45
George Muller, Celgene
The discovery of apremilast.
12.30
Lunch (Including SMR AGM 13.10-13.30)
Session 2 - Chair: Diane Coe, GSK
13.30
David Fox, Pfizer
The discovery of a second generation long-acting PDE5 inhibitor.

14.15
Simon Hodgson, GSK
The discovery of a dual H1/H3 antagonist for allergic rhinitis.

15.00
Tea
Session 3 - Chair: David Fox, Pfizer
15.30
Karl Gibson, Pfizer
The discovery of a progesterone receptor antagonist for endometriosis.
16.15
Mairi Gibson, GSK
Second generation EP1 antagonists for the treatment of pain.
17.00
Close

Wednesday, 14 October 2009

ChEMBL interface: Call for Testers

So, we have an initial interface for the ChEMBL SAR data, and we are looking for some interested people to do some testing, find issues with different OS, browsers, java versions, etc. The kinase SARfari testing we did was very helpful, and many, many thanks to those of you that helped, but rest assured, we will mail you for feedback, bugs, etc.

If you wish to take part, please mail us

Kinase SARfari has been updated

We have released an update to Kinase Sarfari, the major changes are:

Frontend Changes

  1. Compound report card now displays smiles, inchi, inchi_key
  2. Bioactivity data download now includes smiles
  3. User guide updated
  4. Starlite references changed to ChEMBL

Backend Changes

  1. Migrated kinasesarfari schema from chemdev to chempro (an internal trifle, but important to us ;)
  2. Schema clean up

Thanks for all the feedback!

Thursday, 1 October 2009

New Drug Approvals - Pt. XIX - Pralatrexate (Folotyn)



Also approved on September 25th was Pralatrexate (tradename Folotyn). Pralatrexate is the first drug approved for the treatment of Peripheral T-Cell Lymphoma (PTCL), an aggressive form of non-Hodgkins lymphoma. Lymphoma is a cancer that begins in the lymphocytes of the immune system. PTCL is a rare disease, occurring in around 9,500 patients each year in the United States.
Pralatrexate, also known as PDX, is a folic analog that competitively inhibits dihydrofolate reductase (DHFR). Since Pralatrexate blocks the use/function of a metabolite, it is also an antimetabolite. Pralatraxate has high affinity for the folate transporter SLC19A1 (also known as RFC-1), and so is an example of a drug that is 'actively transported', and is also a substrate for polyglutamation by the enzyme folylpolyglutamate synthase (FPGS). Once polyglutamated Pralatrexate has a prolonged intracellular half-life, giving prolonged action in malignant cells. Pralatrexate is related to several other drugs, most notably Methotrexate, and 'old' launched drug, and also the clinical stage compounds - Ketotrexate, Edatrexate, and also the antiprotozoal agent Trimetrexate, all of which are DHFR inhibitors.
Pralatrexate is a polar, racemic small molecule (Molecular Weight of 477.5 g.mol-1), soluble in aqueous solutions. Pralatrexate is a mixture of diastereomers (stereoisomers that are not enantiomers, i.e. they are non-superimposable). Diastereomers can have different physical properties biological activities, and different reactivity. Pralatrexate has a volume of distribution (Vd) of 105L and 37L for the S- and R-diastereomers, respectively, a plasma protein binding (ppb) of 67%, a systemic clearance of 417 mL.min-1 (S-diastereomer) and 191 mL.min-1 (R-diastereomer), and an elimination half-life (T1/2)of 12-18 hours. Pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases, and has low potential to induce or inhibit the activity of CYP450 isozymes - elimination is primarily of unchanged drug in urine.
The recommended dosing of Pralatrexate is 30 mg.m-2 administrated as an intravenous injection once weekly for 6 weeks in 7-week cycles. The full prescribing information can be found here.

The structure (2S)-2-[[4-[(1RS)-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid is a folate analog in which the hydroxyl group of the pyrimidine ring has been replaced by an amine, and the central amino group of the molecule has been replaced by a stereocenter carbon with a methylacethylene attached to it (which may undergo nucleophilic atack). Pralatrexate diastereomers differ in configuration at this stereocenter only, and so they are also epimers.
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The license holder is Allos Therapeutics, Inc. and the product website is www.folotyn.com.

Monday, 28 September 2009

New Drug Approvals - Pt. XVIII - Ustekinumab (Stelara)

Recently approved by the FDA, on September 25th 2009, was Ustekinumab, marketed under the trade name Stelara. Ustekinumab, previously known as CNTO-1275, is a first-in-class injectable biological drug blocking signalling of two distinct interleukins (IL-12 and IL-23) and is indicated for the treatment of adults with moderate to severe plaque psoriasis. Psoriasis (ICD-10: L40) is a complex autoimmune disease, typically leading to the formation of scaly red or silvery-white plaques on the skin. Another drug with the same mechanism as Ustekinumab (blocking IL-12 and IL-23 signalling) is ABT-874, ABT-874 is currently still in clinical trials.
Ustekinumab is dosed as a subcutaneous injection given at weeks 0 and 4, followed subsequently by every-12-week maintenance dosing. The recommended starting dose of is 45 mg for patients weighing 100 kg or less, and 90 mg for patients weighing more than 110 kg (the 45mg dose corresponds to a 0.31 umol dose).
Ustekinumab is is a human IgG1қ monoclonal antibody and is the first drug to target IL-12 and IL-23 cytokines, these are two naturally occurring secreted, heterodimeric proteins (two distinct proteins (themselves derived from two distinct genes) bound in a specific complex), they are involved in inflammatory and immune responses, such as the activation of CD4+ and Natural Killer T-cells. Ustekinumab binds with high affinity and specificity to the p40 protein shared as a common subunit by both IL-12 and IL-23. Through targeting the shared p40 component, Ustekinumab is able to block signalling by both interleukins. IL-12 and IL-23 eventually signal via master inflammatory system regulators tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB).
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The license holder for Ustekinumab is Johnson & Johnson. and the product website is www.stelarainfo.com.

Saturday, 19 September 2009

New Drug Approvals - Pt. XVII - Telavancin (Vibativ)

The latest new drug approval, on 11th September 2009 was Telavancin - which was approved for the treatment of adults with complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive bacteria, including Staphylococcus aureus, both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains. Telavancin is also active against Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus) and Enterococcus faecalis (vancomycin susceptible isolates only). Telavancin is a semisynthetic derivative of Vancomycin. Vancomycin itself is a natural product drug, isolated originally from soil samples in Borneo, and is produced by controlled fermentation of Amycolatopsis orientalis - a member of the Actinobacteria.

Telavancin has a dual mechanism of action, firstly it inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan - the mesh like outer membrane of the bacteria. It achieves this effect in a similar manner to the mechanism of Vancomycin. Vancomycin (and Telavancin) prevent the incorporation of NAM (N-acetylmuramic acid) and NAG (N-acetylglucosamine) subunits into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. Secondly, Telavancin binds to the bacterial membrane and disrupts membrane barrier function.

Telavancin is a lipoglycopeptide antibiotic, and is semisythetic, being a derivative of the natural product Vancomycin, it has a molecular weight of 1755.6g.mol-1, as would be expected from a compound of this size, it comprehensively fails all the components of the Rule-of-Five. Telavancin is lipophillic and as expected, is not highly soluble in water. Following injection, Telavancin has a volume of distribution of 145mL/kg, a plasma half-life of 8hr and a clearance of 13.9mL/hr/kg.

Telavancin is available in the form of a reconstitutable powder for injection. Recommended dosage and full prescribing information can be found here. A course of treatment usually last seven or fourteen days and is a once daily dose of 10mg/kg (given as an hour long infusion). For a 'typical' adult of mass 70kg, this is a once daily dose of 700mg, this equates to a relatively large molar dosage (ca. 400umol).

Telavancin has a boxed warning.

Televancin has a complicated tricyclic structure, there are seven amino-acids as the core of the structure (the 'peptide' part of the lipoglycopeptide name), there are two sugar rings (the 'glyco' part of the name), and then, on the right hand part of the image above, a long lipophillic chain (the 'lipo' part of the lipoglycopeptide name). The biosynthesis of the parent natural product is fascinating, and is covered here. The specific differences of Telavancin compared to Vancomycin are the addition of the lipophillic alkyl chain, and the addition of the phosphate group (in the bottom right of the image). The glycopeptide antibiotic class of drugs include other Vancomycin derivatives, for example, Teicoplanin (launched as Targocid), Oritavancin (phase III trials), Dalbavancin (phase III trials) and the more chemically dissimilar Ramoplanin (phase III trials).

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The license holder is Theravance and www.vibativ.com is the product website.

Thursday, 17 September 2009

EU Innovative Medicines Initiative (IMI) 2nd call

The European Commission and EFPIA (European Federation of Pharmaceutical Industries and Associations) has recently announced the 2nd round of the Innovative Medicines Initiative (IMI) scheme, the amount of funding available is quite substantial, but arguably more important to the research community is the embracing of open data and services, and in particular coordinated pre-competitive activities (there is a lovely recent paper on these sort of activities here, a subscription may be required)
%J Nature Rev. Drug Discov. 
%D 2009
%P 701-708
%T Lowering industry firewalls: pre-competitive informatics initiatives in drug discovery
%A Barnes MR
%A Harland L
%A Foord SM
%A Hall MD
%A Dix I
%A Thomas S
%A Williams-Jones BI
%A Brouwer CR

To quote from the EU Commissioner of Science and Research, Janez Potocnik.

"We should see results from this exciting new research mechanism very soon and [...] new innovative medicines should reach European patients faster"

To quote from Bill and Ted

"Most excellent!"

The website for IMI is http://imi.europa.eu, and details of the second call are here

Sunday, 13 September 2009

Kinase SARfari is now live

Kinase SARfari is now live and online - free and open to one and all. We'll keep an eye on machine logs for the next couple of weeks, and so we may bounce it now and then. Please let us know if you have any issues with using it, and please tell us OS and browser versions for any bug reports.

The URL for kinase SARfari is http://www.sarfari.org/kinasesarfari

Full source code is also available, licensed under a very permissive Creative Commons licence. Mail us if you want this, but as soon as we sort out our downloads area, it will also be available from there.

The data in the backend database is in the process of being updated to a more recent data cut, and when this is done, we'll post details. We're also resurrecting the rhodopsin-like GPCR version. There is also an email address for sarfari support issues.