Clustering of a few chemical databases

Above is a PCA plot of a number (17) of databases contained within UniChem (click image to make it bigger). The plot contains 30 odd % of the variance, so certainly not the complete picture, and pretty close to the dignity level of plotting in 2D! Check out https://www.ebi.ac.uk/unichem for more details on the databases and versions, the distance metric reflects the fraction of shared standard InChI keys.

Anyway, it's pretty interesting, there are arguably three arms to this...

• Top left - screening compound databases (zinc, euos and emolecules)
• Bottom centre - patent databases (patents, ibm and surechem)
• Centre right - drug databases (drugbank, et al)

In the middle is Chembl itself, which sort of makes sense, as there will be fractionally more overlap with patent db's, available compounds, and drugs.

USAN Watch: June 2013

The USANs for June 2013 have recently been published.

USAN	Research Code	InChIKey (Parent)	Drug Class	Therapeutic class	Target
beraprost	ML-1229	CTPOHARTNNSRSR-OUKQBFOZSA-N	therapeutic	synthetic small molecule	PGI2R
esketamine hydrochloride		YQEZLKZALYSWHR-ZDUSSCGKSA-N	therapeutic	synthetic small molecule	NMDAR
evolocumab	AMG-145	n/a	therapeutic	monoclonal antibody	PCSK9
idelalisib	GS-1101, CAL-101	IFSDAJWBUCMOAH-HNNXBMFYSA-N	therapeutic	synthetic small molecule	PI3K
rivipansel, rivipansel hydrochloride	GMI-1070, PF-06460031	n/a	therapeutic	natural product-derived small molecule	selectin

New Drug Approvals 2013 - Pt. IX - Dabrafenib mesylate (Tafinlar®)

ATC code: L01XE15
Wikipedia: Dabrafenib


On May 29th 2013 the FDA approved dabrafenib mesylate (trade name: Tafinlar®, research codes GSK-2118436A and GSK-2118436B) for the treatment of patients with unresectable metastatic melanoma harbouring the BRAF V600E mutation. In clinical trials, dabrafenib showed improved progression-free survival (PFS) over the comparator dacarbazine (median PFS 5.1 months for dabrafenib compared to 2.7 months for dacarbazine). Moreover, in a multicentre open-label Phase II trial dabrafenib showed effectiveness on brain metastases of melanoma regardless of whether the patients had been previously treated.

As with the previously approved BRAF inhibitor, vemurafenib, the major side effect of dabrafenib is the emergence of malignant cutaneous squamous cell carcinomas and keratoacanthomas.

The main molecular target for dabrafenib is the human mutant serine/threonine kinase, BRAF (Uniprot for wild type protein: P15056). Dabrafenib potently inhibits multiple mutant BRAF species including V600E at 0.65 nM, V600K at 0.5 nM and V600D at 1.84 nM. It also inhibits wild type BRAF at 3.2 nM and wild type CRAF at 5 nM.

Dabrafenib is administered orally as capsules containing the dabrafenib mesylate salt. Dabrafenib freebase (ChEMBL:CHEMBL2028663) has a molecular weight of 519.6 and AlogP of 5.38. The molecular formula of dabrafenib is C23H20F3N5O2S2. After oral administration, the median time to reach peak plasma concentration (Tmax) is 2 hours; the mean absolute bioavailability is 95% and the mean terminal half-life is 8 hours after oral administration.

Tafinlar® is produced by Glaxosmithkline

The full Prescribing Information is here

bissan

Meeting: Computational Electrostatics for Biological Applications (CEBA)

Computational Electrostatics for Biological Applications (CEBA) is an international meeting joining researchers in computational disciplines aiming at discussing and exploring different approaches to improve the electrostatics calculations in the Molecular Biology field. The scope of the meeting is quite broad. However, a special focus on theoretical, numerical and modeling aspects of the Poisson-Boltzmann equation and its applications to the NanoBiotechnology field will be given.

The conference website is here

PhD positions available at EMBL-EBI

The joy in submitting a PhD is insurmountable, and some say it feels like going to heaven (n.b. Ben!).

Anyway, four EMBL-EBI faculty are recruiting PhD students in this round of the EMBL International PhD Programme. The deadline for submissions is 17th June 2013 - so not long away now - get your skates on if you are interested. These four year studentships will be available from October 2013 onwards.

The labs taking students this round are:

• Alex Bateman's group.
• John Overington's group.
• Chris Steinbeck's group.
• Sarah Teichmann's group.

Click on the links above to see current group research interests.

There are also other excellent PhD studentship opportunities available at EMBL in Heidelberg and various of the other EMBL Outstations - for details see here.

jpo

New Drug Approvals 2013 - Pt. VIII - Fluticasone furoate and Vilanterol (Breo ElliptaTM)

ATC Code: R03AK10
Wikipedia: Vilanterol

On May 10^th, the FDA approved Vilanterol (Tradename: Breo Ellipta; Research Code: GW-642444M), a long-acting beta₂-adrenergic agonist, in combination with the already approved fluticasone furoate, an inhaled corticosteroid, for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is characterised by the occurrence of chronic bronchitis or emphysema, a pair of commonly co-existing diseases of the lungs in which the airways become narrowed. Bronchial spasms, a sudden constriction of the muscles in the walls of the bronchioles, occur frequently in COPD.

Vilanterol is a new long-acting beta₂ receptor agonist that through the activation of the beta₂ adrenergic receptors present in the bronchial smooth muscle, leads to bronchodilation, and consequently eases the symptoms of COPD.

The beta₂ adrenergeic receptor (Uniprot: P07550; ChEMBL: CHEMBL210) belongs to the G-protein coupled receptor (GPCR) type 1 family, and binds the endogenous neurotransmitter adrenaline. Since it is coupled to a Gs protein, its activation leads ultimately to an increase in cyclic AMP (cAMP), which cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

>ADRB2_HUMAN Beta-2 adrenergic receptor
MGQPGNGSAFLLAPNGSHAPDHDVTQERDEVWVVGMGIVMSLIVLAIVFGNVLVITAIAK
FERLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFGNFWCEFWTSIDVLCVTAS
IETLCVIAVDRYFAITSPFKYQSLLTKNKARVIILMVWIVSGLTSFLPIQMHWYRATHQE
AINCYANETCCDFFTNQAYAIASSIVSFYVPLVIMVFVYSRVFQEAKRQLQKIDKSEGRF
HVQNLSQVEQDGRTGHGLRRSSKFCLKEHKALKTLGIIMGTFTLCWLPFFIVNIVHVIQD
NLIRKEVYILLNWIGYVNSGFNPLIYCRSPDFRIAFQELLCLRRSSLKAYGNGYSSNGNT
GEQSGYHVEQEKENKLLCEDLPGTEDFVGHQGTVPSDNIDSQGRNCSTNDSLL

There are 11 resolved 3D structures for this protein with vary degrees of resolution (2.40 to 3.50 &#197) and different fusion protocols. For instance, 3ny8, is a fused protein of the human beta₂ adrenergeic receptor with Lysozyme Bacteriophage T4, with a resolution of 2.84 &#197 and an inverse agonist bound to it (ICI-118,551, ChEMBL: CHEMBL513389):

The full list of PDBe entries can be found here.

The -terol USAN/INN stem covers bronchodilators structurally related with phenethylamine. Members of these class include for example Salmeterol (ChEMBL: CHEMBL1263), Formoterol (ChEMBL: CHEMBL1256786) and Indacaterol (ChEMBL: CHEMBL1095777), all long-acting beta₂-adrenergic agonists also approved for the management of COPD. For a full list of compounds check ChEMBL.

Vilanterol (IUPAC Name: 4-[(1R)-2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol; Canonical smiles: OCc1cc(ccc1O)[C@@H](O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl; ChEMBL: CHEMBL1198857; PubChem: 10184665; ChemSpider: 8360167; Standard InChI Key: DAFYYTQWSAWIGS-DEOSSOPVSA-N) is a synthetic small molecule, with a molecular weight of 486.4 Da, 6 hydrogen bond acceptors, 4 hydrogen bond donors, and has an ALogP of 4.22. The compound is therefore fully compliant with the rule of five.

Breo Ellipta is available as a dry powder inhaler and the recommended daily dose is one inhalation of fluticasone furoate/vilanterol 100/25 mcg. Following inhalation, vilanterol peak plasma concentrations are reached within 10 minutes, and its absolute bioavailability is 27.3%. At steady state, following intravenous administration, the mean volume of distribution of vilanterol (Vd/F) was 165L in healthy subjects. Vilanterol is strongly bound to human plasma proteins (93.3 %).

Vilanterol is primarily metabolized in the liver by CYP3A4. Therefore, concomitant administration of potent CYP3A4 inhibitors should be avoided. Vilanterol metabolites are primarily excreted in urine (70%) and feces (30%). The effective half-life (t_1/2) for Vilanterol is approximately 21 hours in patients with COPD.

Breo Ellipta has been issued with a black box warning due to Vilanterol increased risk of asthma-related death, a known risk to all long-acting beta₂-adrenergic agonists.

The license holder for Breo Ellipta^TM is GlaxoSmithKline, and the full prescribing information can be found here.

Paper: In silico applications of bioisosterism in contemporary medicinal chemistry practice

If you were looking for an up-to-date review of computational applications of bioisosterism in medicinal chemistry, then look no further. After an overview of the history and evolution of bioisosterism, the paper reports the various attempts aiming to capture and quantify it, as well as to disseminate its examples in the context of modern computer-aided drug discovery.

Link to the paper here. 

%A G. Papadatos
%A N. Brown
%T In silico applications of bioisosterism in contemporary medicinal chemistry practice
%J WIREs Computational Molecular Science
%D 2013
%O doi.10.1002/wcms.1148

George  

New Drug Approvals 2013 - Pt. VII - Radium Ra 223 dichloride (Xofigo)

ATC code:
Wikipedia: Xofigo

On May 15th, 2013 the FDA approved the alpha particle-emitting Radium Ra 223 dichloride (Xofigo) as a radiotherapeutic agent for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. The therapeutic component is the alpha particle-emiting Radium 223 isotope. It mimics calcium and binds to bone minerals is areas of rapid cell division, where it preferentially affects cancer cells. The radiation causes high levels of DNA double-strand breaks in adjacent cells, causing the killing of rapidly dividing cells, such as bone metastases.

After intravenous injection, Ra 223 is rapidly cleared from the blood and distributed primarily into bone or is excreted into intestine. The levels of radioactivity detected in the blood rapidly decrease and, at 24 hours, reach less than 1% of the administered dose. The alpha particle emission range of Ra 223 is 100 micrometers which protects against damage to normal surrounding tissue.

The molecular weight of Ra 223 dichloride, 223RaCl2, is 293.9 g/mol. Ra 223 has a half-life of 11.4 days and an activity of 1.9 MBq (51.4 microcurie)/ng.

In Phase 3 clinical trials, Xofigo increased survival to 14.9 months as compared to 11.3 for placebo.

Xofigo is a product of Bayer The Prescribing Information can be found here.

PKIS data in ChEMBL

The Protein Kinase Inhibitor Set (PKIS) made available by GSK was recently mentioned on In the Pipeline. In collaboration with GSK, we are making the data being generated on these compounds available via the ChEMBL database. We are also creating a portal for the compound set, where the structures can be browsed and downloaded, direct links to the data are provided and useful information can be posted. A preliminary version is available here: feedback would be appreciated.

The data generated on the PKIS set and deposited in ChEMBL may be downloaded in CSV format here (note that the Luciferase dataset described in the recent PLoS paper will be in the next release of ChEMBL). Alternatively, to view the data in the ChEMBL web interface, follow these steps:

• On the home page, enter 'GSK_PKIS' in the search box and click on the 'Assays' button...

• On the 'Please select...' menu on the right, choose 'Display Bioactivities'...

• Again, on the 'Please select...' menu on the right, choose 'Download All Data (TAB)' to download the data as a tab-separated spreadsheet...

To complement these datasets, other data for these compounds held in ChEMBL, such as that extracted from the medicinal-chemistry literature, may be downloaded in CSV format here. 

For information about obtaining the compound set for screening, please contact Bill Zuercher at GSK.

ChEMBL_16 Released

We are pleased to announce the release of ChEMBL_16. This version of the database was prepared on 7th May 2013 and contains:

1,481,473 compound records
1,295,510 compounds (of which 1,292,344 have mol files)
11,420,351 activities
712,836 assays
9,844 targets
50,095 documents
19 activity data sources

You can download the data from the ChEMBL ftpsite and do not forget to read the ChEMBL_16 Release Notes

Data changes since the last release
ChEMBL_16 includes the Millipore Kinase Screening publication (CHEMBL2218924), which is kinase screening panel data set focused on 158 known kinase inhibitors and the OSDD Malaria Screening dataset (CHEMBL2113921), which is a set of anti-malarial compounds and bioactivity data provided by the OSDD Malaria consortium. 

In addition to the our regular publication and dataset updates we are now also loading supplementary bioactivity datasets. In this example the original paper from GSK was published in 2010 (CHEMBL1157114) and with the release of ChEMBL_16 we now provide 2 supplementary datasets (CHEMBL2218064 and CHEMBL2094195). You can see the original paper an supplemenatry datasets in screenshot below (this also demonstrates the new document search functionality we have added to the interface):

We are would like grow our supplementary bioactivity datasets, so please get in touch if you have any similar data you would like to deposit in the ChEMBL database. Stefan Senger from GSK, has put together the following slides, which provide more details on the pros and pros of depositing  supplementary bioactivity data. (Also thanks Derek Lowe over at In The Pipeline for the following blog post).

Interface changes since the last release:
We have made a number changes to the interface which are listed below:

• Document Search - Submit a keyword search against journal articles and datasets loaded into the database
• Browse Targets - We have improved the tree browser on protein classification and organism browser targets page 
• Browse Drugs - Now allows searching on USAN stem and ATC code definitions
• Updated FAQ pages - see here
• Target Report Card - Now contains a target relation section, providing links between targets sharing protein components. The target report card also includes links to CREDO and TIMBAL databases
• Compound Report Card - Includes a link to NCI Resolver service, to retrieve additional synonyms for a compound

In addition to our regular set of downloads (Oracle, MySQL, PostgreSQL) you will also find RDF version on the ChEMBL database. The current version is 16.0 and the files are available to download here. You can expect some minor changes in the RDF between now and the ChEMBL_17 release and these will be represented by increments in the minor version number

The ChEMBL Team