One of our old friends, Dave Leahy, has recently launched a site that contains a very large set of QSAR models trained and validated automatically from the ChEMBL data. Of course, not all ChEMBL assays will lead to reliable, predictive models, but www.openqsar.org contains ca. 13,000 stable models from ChEMBL_02. The ability to in silico profile the potential bioactivity and liabilities of molecules is a very exciting one.
"Open QSAR" is a web based platform for building, viewing and managing huge QSAR model libraries, and is intended to facilitate, and provide a platform for, Open Source Drug Discovery. The web server allows anyone to submit molecules to get predicted properties using existing Open QSAR models. This is free but the results are viewable by anyone.
People interested in the QSAR models in OpenQSAR may also wish to look at Molplex, a company providing compounds for screening, and also high content screening services.
Some of the ChEMBL team are in Tokyo, Japan for the week of 14th to 18th March 2011. We are there for some training with a valued collaborator. We have some spaces in our schedule so we could visit and talk if there is interest. We have a native Japanese speaker in our group, and so we can present in both Japanese and English. If you would like us to visit you please mail.
Dabigatran etexilate has been approved by the FDA on October 19th 2010. Dabigatran etexilate (also known as BIBR-1048 for Dabigatran etexilate and BIBR-953 for Dabigatran) is approved for the treatment of patients with atrial fibrillation at risk of embolism or stroke. Dabigatran etexilate is a first-in-class (for the US) oral drug preventing blood clotting and stroke by direct inhibition of thrombin and is marketed under the trade name Pradaxa in Europe and the US, and Pradax in certain other territories. In Europe, an earlier oral direct thrombin inhibitor Xemelagatran (trademark:Exanta trademark:Exarta also known as H376/95) was approved, but subsequently was withdrawn due to commercial and perceived safety issues.
The formation of blood clots in the circulation can cause embolism or stroke (or CVA) if other risk factors are present. Depending on the number of risk factors, the risk of suffering a stroke increases up to 7-fold in patients with atrial fibrillation. Patients with atrial fibrillation are therefore often treated with the anticoagulant warfarin (ChEMBL: 494165) to prevent the formation of blood clots, Warfarin is a drug with a poor therapeutic index, and also shows substantial intra-patient variability due to underlying genetic differences, with subsequent required regular patient monitoring.
Dabigatran etexilate is converted to the active drug Dabigatran. It inhibits blood clotting through direct inhibition of thrombin (Uniprot: P00734) and has a larger therapeutic window than warfarin (which is an irreversible inhibitor of vitamin K epoxide reductase). Thrombin is a key serine protease in the blood clotting cascade, activating coagulation factors Factor V, Factor VIII, Factor XI and Factor XIII as well as cleaving fibrinogen and thus transforming it to the blood clot forming fibrin (also known as Factor Ia) (Uniprot: P02679). There are many known structures of thrombin, both in prothrombin and mature thrombin forms (for example see PDBe:2bvs).
Thrombin is a trypsin-like serine proteinase (Pfam:PF00089), and cleaves after arginine (and lysine) residues at the P1 position in substrates; Dabigatran is a substrate mimic (a peptidomimetic), with the phenylamidine mimicking the arginine sidechain.
Upon absorpotion, Dabigatran etexilate is readily metabolized to the active drug Dabigatran by ester hydrolysis at two distinct positions (therefore Dabigatran is dosed as a double prodrug). The charged groups of Dabigatran (the amidine and carboxylic acid) are poorly absorbed across membranes, and therefor the lipophilic ester and carbamate are added to mask these groups during oral dosing and absorption. Dabigatran is further metabolized to four different acyl glucuronides which are equally active as thrombin inhibitors. The absolute oral biovailability of Dabigatran (dosed as the prodrug) is 3-7%. The fraction of dabigatran bound to plasma proteins (ppb) is ~35% and volume of distribution (Vd) is 50-70L, clearance is primarily renal with a half-life (t1/2) of 12-14 hours.
Dabigatran etexilate is recommended for twice daily administration of 300mg (in two 150mg doses).
The newly published CXCR4 ligand complex structures are now released in PDBe. In total there are 5 new PDB entries (3odu, 3oe0, 3oe6, 3oe8 and 3oe9) but 9 distinct new chain structures (some PDB entries have multiple copies of CXCR4 in the asymmetric unit). All structures are complexed with a ligand, either a small molecule antagonist, called IT1t (pictured below), or a medium sized peptide antagonist, CVX-15 (Arg-Arg-Nal-Cys-Tyr-Gln-Lys-dPro-Pro-Tyr-Arg-Cit-Cys-Arg-Gly-dPro).
Interested readers are also directed to an excellent blog http://emeraldbiostructures.com/gpcrblog/ with a deep focus on structural biology, protein chemistry, engineering of GPCRs. There are reported to be several more GPCR structures currently solved, including S1P and D2.
Here is a table of the new structures from PDBe. The GPCR structure table has been updated (but you will probably need to download this in order to make sense of it).
The 2.5 A structure of the CXCR4 chemokine receptor in complex with small molecule antagonist IT1t
x-ray diffraction
2.5
2010/10/27
Fitting all these CXCR4 structures together, gives 239 equivalenced Calpha atoms (using an equivalence cutoff of 4.5Angstrom). The processing of the files for the fit included removal of the lysozyme insert domain and also any extraneous ligands and waters. When MDS is performed on the RMSD matrix, the major determinant of the structural similarity is the bound ligand, (not surprisingly given the difference in size of IT1t and CVX-15).
Here are the overlaid coordinates. 3oduA, 3oduB, 3oe0A, 3oe6A, 3oe8A, 3oe8B, 3oe8C, 3oe9A, 3oe9B. As noted above, the coordinate sets have been substantially edited compared to the original PDB entries.
Below is the joy formatted sequence of 3oduA - lower case=non-core, UPPER case=core, red=helix, blue=sheet, italic=positive phi.
%T Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists
%J Science
%D 2010
%V 330
%A B. Wu
%A E.Y.T. Chien
%A C.D. Mol
%A G. Fenalti
%A W. Liu
%A V. Katritch
%A R. Abagyan
%A A. Brooun
%A P. Wells
%A F.C. Bi
%A D.J. Hamel
%A P. Kuhn
%A T.M. Handel
%A V. Cherezov
%A R.C. Stevens
%O DOI: 10.1126/science.1194396
(PDBe
On the 3rd November, the structure of human D3 receptor complexed with Eticlopride was released (PDBe:3pbl)
As mentioned in a previous post, we now have some immediately available positions within our team for some short-term contractors (6 months to 1 year). These are for two collaborative (and very exciting) industry projects, and require good bioinformatics knowledge, programming in perl (or equivalent) knowledge of SQL, and database querying and integration. Previous experience in either target assessment, or computational studies of ADMET processes would be greatly beneficial (see below).
One position will be to work on 'druggability' calculations, the second will be connected with comparative genomics of ADMET systems - building a prototype ADMET SARfari (see the SARfari tags on the ChEMBL-og for more details on SARfari). Positions are full time and require a pre-existing right of residence and also pre-existing right to work within the United Kingdom. Pay and general conditions are subject to negotiation. Work will be based at our Hinxton campus site. More details are available on request.
We will post additional information on LinkedIn in a day or so.....
We will soon post on the EMBL recruitment pages, details of a new post within ChEMBL - a database developer for a very exciting pan-European collaboration called EU-OPENSCREEN. EU-OPENSCREEN is one of a set of large-scale Research Infrastructure projects called 'ESFRIs', and EU-OPENSCREEN is connected with establishing an infrastructure of screening centers, compound collections and associated 'Open' Chemical Biology Data. EU-OPENSCREEN has recently started, and is in the so-called 'Preparatory Phase'.
The job will require someone with good technical informatics and scientific skills connected with database design and integration, biological screening, bioinformatics and chemoinformatics, data security, and will require travel to European and U.S. collaborator labs.
An associated EU-OPENSCREEN post within the Steinbeck group at the EBI, on Data Standards, Ontologies, etc., will also be announced shortly.
When the position is live on the EMBL recruitment site, I'll post another reminder post.
Applications have just opened for PhD studentships at the Institute of Cancer Research [See here].
We have a studentship on applying chemogenomics and in-silico network biology to discover new cancer drug targets from siRNA screening data. Details on the project can be found here.
The student will be imbedded within the Cancer Therapeutics Unit in Sutton, with time spent at the Chlesea ICR site in Dr. Marketa Zvelebil's team. This is an exciting studentship because it is applying the two exciting fields of chemogenomics and network biology, and working very closely with biologists and chemists with the ICR. New cancer targets discovered have the opportunity to be validated and progressed within the Cancer Therapeutics Unit.
This is a four year MRC funded research studentship, please check you are eligible before applying.
We regularly offer internships within the ChEMBL group, these are typically for between three and six months. We receive about five to ten applications per week, so only a small fraction of applications are successful. We try and match these against project ideas we have, available space, and our limited budget. Here is some advice for those wishing to apply.
Please note - working as an intern at any EMBL lab may negatively affect applications for study as a PhD student at EMBL - please check the regulations carefully if you plan to apply for a PhD.
Please try and be accurate about the group you are applying to, we understand that you are probably looking at many opportunities, but if you mention a completely different scientific area, PI name, or have a very vague and general application, we will be unable to consider your application further.
Attach a current and accurate cv (please do not feel under pressure to limit this to two pages) with your initial application. Be accurate with the description of your skills and interests.
We circulate the applications amongst the ChEMBL group, and then short-list candidates for a skype video call, where we will have a half-hour interview, including some technical tests.
The group use Apple hardware for desktop machines and you will need to be able to use UNIX (in one its many forms), command line, and standard office tools (MS Office, or equivalent). You will not be able to bring your own computer/licensed software to perform work with us.
We will pay you a modest stipend while you are here, but you need to fund your own travel to and from the United Kingdom where required.
We do not have time to reply to, or provide feedback on, every application we receive, sorry.
We have a broad range of project ideas, not just those listed on the page linked to below; so we welcome applications from bioinformaticians, chemoinformaticians, structural biologists, web developers, knowledge modelling and those with drug discovery backgrounds.
Details on the EMBL-EBI's internship program are found here; however, please note that there are some contradictions in the current EBI website material - specifically, we welcome applications from all nationalities.
As mentioned in a previous post, we now have some immediately available positions within our team for some short-term contractors (6 months to 1 year). These are for two collaborative (and very exciting) industry projects, and require good bioinformatics knowledge, programming in perl (or equivalent) knowledge of SQL, and database querying and integration. Previous experience in either target assessment, or computational studies of ADMET processes would be greatly beneficial (see below).
We will soon post on the EMBL recruitment pages, details of a new post within ChEMBL - a database developer for a very exciting pan-European collaboration called EU-OPENSCREEN. EU-OPENSCREEN is one of a set of large-scale Research Infrastructure projects called 'ESFRIs', and EU-OPENSCREEN is connected with establishing an infrastructure of screening centers, compound collections and associated 'Open' Chemical Biology Data. EU-OPENSCREEN has recently started, and is in the so-called 'Preparatory Phase'.
Applications have just opened for PhD studentships at the Institute of Cancer Research [See here]. 
We regularly offer internships within the ChEMBL group, these are typically for between three and six months. We receive about five to ten applications per week, so only a small fraction of applications are successful. We try and match these against project ideas we have, available space, and our limited budget. Here is some advice for those wishing to apply.
