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

Thursday, 19 August 2010

SMR Meeting On Epigenetics - 22nd September 2010


Drat! It's almost as if the SMR committee look at my Google calendar and book all their meetings on days when I'm otherwise occupied.....

Anyway, on Wednesday September 22nd 2010 the SMR are holding a meeting on Epigenetics, one of the hottest current areas of disease biology, at the NHLI, further details here.

Tuesday, 17 August 2010

2010 New Drug Approval - Pt. X - Ulipristal Acetate (Ella)



ATC code: G03AD02

The most recent approval by FDA is Ulipristal Acetate, approved on August 13th 2010 under the trade name Ella. Ulipristal Acetate (previously known by the research code CDB-2914 or VA-2914) is a progesterone agonist/antagonist emergency contraceptive, indicated for prevention of pregnancy following unprotected intercourse or known or suspected contraceptive failure.
This drug is a selective progesterone receptor modulator (SPRM) with antagonist and partial agonist effects (a progesterone agonist/antagonist) at the progesterone receptor (PR, NR3C3) (Uniprot code: P06401). The Progesterone Receptor is a member of a very significant family of proteins for drug discovery, the Nuclear Receptors, a family of around 50 genes which are transcription factors, the transcription by NRs is usually ligand regulated. Ulipristal Acetate prevents progesterone, the endogenous ligand, from occupying its receptor. Ulpristal Acetate binds in the ligand binding domain (LBD) of PR (PFAM: PF00104).

There are several structures known of PR complexed with ligands, a representative one is (PDB: 3D90). Ulipristal Acetate will compete with Levonorgestrel, another progestagen available on the market, which is approved for use up to three days post-intercourse as opposed to five days in the case of Ulipristal Acetate.
Ulipristal Acetate is a small-molecule, natural product derived drug (Molecular Weight 475.6 g.mol-1), Rule-of-Five compliant and it is delivered as a tablet. Ulispristal Acetate is highly bound to plasma proteins (>94%), including high density lipoprotein, alpha-1-acid glycoprotein, and albumin. It is metabolized to mono- and di-demethylated metabolites, mostly by CYP3A4; the mono-demethylated metabolite pharmacologically active. Ulpristal Acetate shows high affinity for the related nuclear receptor - glucocorticoid receptor (GR, NR3C1). The terminal half-life of Ulipristal Acetate is ca. 32 hours. The recommended dosage is one tablet (30 mg) taken orally, with or without food, as soon as possible, within 120 hours (five days) after unprotected intercourse or a known or suspected contraceptive failure.
The full prescribing information can be found here.
The structure 17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione is a synthetic progestagen and is thus very similar to progesterone. Like other steroid hormones of this class, Ulipristal Acetate is characterized by its basic 21-carbon skeleton, i.e., four interconnected cyclic hydrocarbons with two methyl branches and a ketone. In this particular case, one of the methyl groups is replaced by a substituted aromatic amine.
NAME="Ulipristal Acetate"
TRADEMARK_NAME="Ella"
ATC_code= NA
SMILES="CC(=O)C1(CCC2C1(CC(C3=C4CCC(=O)C=C4CCC23)C5=CC=C
(C=C5)N(C)C)C)OC(=O)C"
InChI="InChI=1S/C30H37NO4/c1-18(32)30(35-19(2)33)15-14-27
-25-12-8-21-16-23(34)11-13-24(21)28(25)26(17-29(27,30)3)
20-6-9-22(10-7-20)31(4)5/h6-7,9-10,16,25-27H,8,11-15,17H2,
1-5H3/t25-,26+,27-,29-,30-/m0/s1"
ChemDraw=Ulipristal_Acetate.cdx
The license holder is Laboratoire HRA Pharma.

Monday, 16 August 2010

Wednesday, 11 August 2010

Deadline for ESPOD Project on Malaria Target Discovery Is Approaching....


A reminder that the deadline for the application for the EMBL-EBI/Sanger ESPOD fellowships is fast approaching - including that for the exciting Overington/Rayner malaria project - (the final date for applications is August 15th 2010 in fact). So if you are interested, please send in your completed application!

Tuesday, 3 August 2010

ChEMBL Resources for Drug Discovery Course - Feb 2011


We have penned into our diaries the dates of Monday February 14th 2011 thru Friday February 18th 2011 for the second ChEMBL residential training course. This will be held on campus here at Hinxton, registration and details of the sessions to be covered will appear on the EBI website shortly.

2010 year was our first course, and we had to prepare a lot of material, etc. but we really enjoyed it, and the 2011 course will be even better.

The image above is from the excellent xkcd.

Monday, 2 August 2010

From One Of Our Collaborators - MoSS+ChEMBL with Bioclipse

Pharmaceutical Knowledge Retrieval through Reasoning of chEMBL RDF” is the title of my master thesis, a twenty-week research project performed at the Department of Pharmaceutical Bioscience at Uppsala University (Prof. Wikberg, supervised by Egon Willighagen). The project aims at using the ChEMBL data with a technology that might be new to some: by using semantic web technologies. The life sciences workbench Bioclipse (doi:10.1186/1471-2105-10-397) has support for several semantic web tools, including RDF, and was used to establish such a connection.

Two aspects were looked at in this study. Firstly, we developed the search functionality for ChEMBL data to use RDF. For this, we took advantage of the RDF-ized ChEMBL knowledgebase (using the data from ChEMBL 02). Secondly, we developed a use case where compounds derived from ChEMBL are analyzed with the substructure mining software MoSS (see the Bioclipse Wiki). Here, we search for common and discriminative substructures within or between kinase families.
Within the context of these two aspects, we developed an application using both the JavaScript and the Wizard functionality in Bioclipse. The above shown wizard shows how various searches for compound-protein interaction can be formulated. Results are shown in the "Results table". The user can then select which data he wants to save, by moving it to the lower table which lists the data that will be saved by this wizard.

A second, more application-targeted Wizard was developed that primarily concentrates on retrieving compounds that bind proteins in a certain kinase family with a given activity type (see below). A histogram can be opened to visualize the distribution of activities. Lower and upper bound values can be selected, for focus, for example, only on that active compounds. A second, identical wizard page is provided to select a second dataset. This allows the user to set up a between-family data set. The saved data can then be used in the MoSS application to find the common and discriminative substructures (not shown).


Benefits of this approach focus on the data interoperability: the RDF technologies are used as uniform and Open Standard access to the ChEMBL data. Using this approach, implementing new search queries is very easy, and does not require one to know anything about the database schema; a common controlled vocabulary (ontology) hides those implementation details. Community standards for such vocabularies are under development, and will integrating the ChEMBL data with other databases and other applications.

Does this sounds interesting to you, or do like to give us feedback? Please send a note to annzi.andersson+chembl@gmail.com . Further details are provided in my blog!

 Sincerely, Annsofie Andersson.