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 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.
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.
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.
There are 11 resolved 3D structures for this protein with vary degrees of resolution (2.40 to 3.50 Å) 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 Å and an inverse agonist bound to it (ICI-118,551, ChEMBL: CHEMBL513389):
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 (t1/2) 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 ElliptaTM is GlaxoSmithKline, and the full prescribing information can be found here.
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.
%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
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.
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.
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
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
We would like to draw attention to readers of The ChEMBL-og to an excellent new paper in the Journal of Cheminformatics, describing the work of Egon Willighagen and co-authors in building the first published, publicly available version of ChEMBL data in RDF form (ChEMBL RDF). The paper also provides details on a number of linked data based applications built on top of an RDF data model, demonstrating the benefits of the data transformation. More details about the paper are provided here and the link to the paper is here.
%T The ChEMBL database as linked open data
%A E.L. Willighagen
%A A. Waagmeester
%A O. Spjuth
%A P. Ansell
%A A.J. Williams
%A V. Tkachenko
%A J. Hastings
%A B. Chen
%A D. J Wild
%J J. Cheminf.
%D 2013
%V 5
%O doi:10.1186/1758-2946-5-23
The ChEMBL group have been funded by the IMI OpenPhacts project to build and deploy an RDF version of ChEMBL (which we are currently calling ChEMBL ChEMBL RDF, sorry for the confusion!). With changes in content and curation closely coupled to, and tracking where required, the current relational schema database.
The ChEMBL group's version is available to download and can be picked up from ChEMBL ftpsite here. We have run some project workshops on the ChEMBL ChEMBL RDF, but otherwise have remained a little bit quiet on its existence as we continue to make a number of small changes, hence the minor version number increments, but 15.8 is the latest version and expect 16.0 this week. Just to be clear, the ChEMBL ChEMBL RDF version we are making available is not the same same as the version being described in the Journal of Cheminformatics paper, and the functionality and queries will be non-interoperable.
Our OpenPhacts involvement is not the only reason we have created an RDF version of the ChEMBL database, we have had many requests from the broader global ChEMBL community to provide RDF in our official release process, so going forward this is something we will commit to providing. We are also keen to minimise the impact of changes we make to the ChEMBL relational model, which has evolved significantly since its first release, (ChEMBL data integrators out there will certainly noticed some pretty big changes in our ChEMBL_15 release). So we also commit to keeping the RDF data model in sync with the relational model.
The joy in submitting a PhD is insurmountable, and some say it feels like going to heaven (n.b. Ben!).
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.
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.
