The ChEMBL-og

A recurring thing we are interested in is classifying the natural ligand/partner of a protein. Having a classification of the 'natural' ligand partner for every human protein would be really useful, and would allow us to ask and more importantly answer quite complex questions in ChEMBL like - ' show me all small molecules that modulate a protein-protein interaction (PPI) at better than 100 nM potency? '. I've had a bit of a dig around the web, but there isn't anything that does exactly what I need (or I'm not smart enough to find it), but I'm sure it must exist, so in the comments section, please post resources and ideas.....

ATC code (partial): J On May 23 rd , the FDA approved Telaprevir (Tradename: Incivek ; Research Code: VX-950, NDA 201917), a Hepatitis C virus NS3 protease  (HCV NS3) inhibitor, for the treatment of chronic hepatitis C virus genotype 1  infection, in combination with peginterferon alfa and ribavirin . HCV is a prolonged infection that affects the liver and is caused by a small positive single-stranded RNA virus , which is transmitted by blood-to-blood contact. Chronic hepatitis C is normally asymptomatic, but may lead to liver fibrosis, and if untreated, potentially fatal liver failure. There is currently no vaccine for this type of hepatitis. Telaprevir is an inhibitor of the hepatitis C virus (HCV) non-structural protein 3 (NS3) protease (ChEMBLID: CHEMBL4893 ; Uniprot ID: A3EZI9 ), a viral protein required for the proteolytic cleavage of the HCV encoded polyprotein (UniProt: P27958 ) into mature forms of the NS4A, NS4B, NS5A and NS5B proteins (NS3 is Unip...

ATC code (partial): J05AG On May 20 th , the FDA approved Rilpivirine (Tradename: Edurant ; Research Code: TMC-278, NDA 202022), an HIV-1 Non-nucleoside reverse transcriptase inhibitor ( NNRTI ), for the treatment of HIV infection in treatment naive patients in combination with other HIV therapies. HIV infection is a serious, and if untreated fatal infection caused by a lentivirus , however due to intensive research, leading to a wide variety of antiviral agents the disease is treatable with a substantial increase in quality of life anticipatable. Rilpivirine is an inhibitor of the essential reverse transcriptase  (RT) enzyme of HIV-1. (ChEMBLID: CHEMBL247 ; Uniprot ID: Q72547 ), a viral protein required for the transcription of the single-stranded RNA genome of HIV-1 into double-stranded DNA - this is the opposite of the classical transcription of DNA into RNA. The RT enzyme is translated as part of a long complex gag-pol polyprotein, and requires specific pr...

Here is a job advert, not for a ChEMBL position, but as part of the (fabulous) IUPHAR-DB project. Senior data curator to assist with the development of the IUPHAR Database ( http://www.iuphar-db.org ) and the British Pharmacological Society Guide to Receptors and Channels ( http://www.brjpharmacol.org/view/0/GRAC.html ). You should hold a PhD or equivalent in Pharmacology, Medicinal Chemistry or a related discipline together with relevant experience in bioinformatics or chemoinformatics. Based in the Queen's Medical Research Institute, you will work independently on a day-to-day basis but in close contact with Professor Tony Harmar, with the database developer and in liaison with IUPHAR and BPS. Closing date is 22nd June. For further information and to apply, click here (see http://bit.ly/kDl7mu ) This post is fixed term until 31st July 2012 with possibility of extension should further funding be obtained.

A simple cross post from the /chemical/structure Blog - the guys have done a great job of setting up a python queryable version of the ChEMBL data. Here's the link !

The Society of Medicines Research (SMR) have a great conference on Transporters in Drug Discovery , being held on Thursday 23rd June 2011, at the Millennium Gloucester Hotel, Kensington, London. Further details are on the SMR website . I (jpo) will actually manage to attend this one, so if anyone wants to meet up, that would be great.

A paper has recently been published, which may be of interest; it covers the use of chemogenomics class data in activities such as target prediction, receptor deorphanisation and so forth. A link the the paper is here . %T Chemogenomics Approaches for Receptor Deorphanization and Extensions of the Chemogenomics Concept to Phenotypic Space %J Curr. Topics Med. Chem. %V 11 %A E. van der Horst %A J.E. Peironcely %A G.J.P. van Westen %A O.O. van den Hoven %A W.R.J.D. Galloway %A D.R. Spring %A J.K. Wegner %A H.W.T. van Vlijmen %A A.P. IJzerman %A John P. Overington %A A. Bender %D 2011

Sign up If you are I interested. Details are here

On the 26th May 2011 new European regulations will come into force, which are aimed at providing website users with a better understanding of data being collected when they visit a website. Covered under these regulations, is the use of cookies , which are small pieces of of text set by some websites and can be used for authentication, saving site preferences/shopping cart selections and storing session information. In short, the cookie is being used to get around the inherently stateless nature of HTTP . There is currently a bit of confusion over what the final regulations and national implementations will be, so the Information Commissioner’s Office (ICO) has drawn up some guidelines , however these will not be finalised until after 26th May 2011 :(. In preparation for these changes we thought we would list the cookies which might be set when a user visits the the ChEMBL interface : Cookie Name Details ci_session Generated by Codeignitor   web application framework and ...

ATC code : A10BH05 On May 2 nd , the FDA approved Linagliptin (BI-1356, trade name Tradjenta , ATC code A10BH05 , ChEMBL ID 237500  NDA 201280), a dipeptidyl peptidase-4 (DPP-4) inhibitor, to treat type II diabetes (OMIM: 125853 ). Linagliptin has been approved for monotherapy or in combination with other medications, in conjunction with exercise and dietary modification. Due to a malfunction in production of or response to insulin, patients with type II diabetes suffer from high blood glucose levels. By inhibiting DPP-4 (Uniprot P27487 , OMIM: 102720 , EC number 3.4.14.5), a cell surface glycoprotein receptor, Linagliptin stabilizes the level of two of its substrates, the intecrins GLP-1 and GIP, gastrointestinal peptide hormones which stimulate insulin release from beta cells of the Islets of Langerhans . Linagliptin has been shown to have a high affinity (Ki 1 nM) for DPP-4 in cell-based fluorescence assays, and to be highly selective...

ATC code (partial): J On May 13 th , the FDA approved Boceprevir (Tradename: Victrelis ; Research Code: SCH-503034, NDA202258), a Hepatitis C virus NS3 protease  (HCV NS3) inhibitor, for the treatment of chronic hepatitis C virus genotype 1  infection, in combination with peginterferon alfa and ribavirin . Chronic hepatitis C genotype 1 is a prolonged infection that affects the liver and is caused by a small single-stranded RNA virus , which is transmitted by blood-to-blood contact. Chronic hepatitis C is normally asymptomatic, but may lead to liver fibrosis, and thus liver failure. Boceprevir is a first-in-class inhibitor of the hepatitis C virus (HCV) non-structural protein 3 (NS3) protease (ChEMBLID: CHEMBL4893 ; Uniprot ID: A3EZI9 ), a viral protein required for the proteolytic cleavage of the HCV encoded polyprotein (UniProt: P27958 ) into mature forms of the NS4A, NS4B, NS5A and NS5B proteins (NS3 is Uniprot: P27958[1027-1657] ). These proteins ar...

Here is a snapshot of the Clinical Development Phase kinase inhibitors we have identified, all 313 of them. Any feedback on the data would be great, so any missing compounds, mismapped synonyms, wrong highest phase data, etc . would really help tune our data discovery approaches for this sort of thing. Please do not send us any proprietary/licensed data that you are not free to share!

The agenda for the first ChEMBL user group meeting is below, we also have some additional speakers on various collaborative projects likely to be of interest to attendees, as extra-meeting items. Many thanks to the speakers and to Brad Sherbourne of Merck for putting this together. The presentations will be a mix of slides and generous discussion time, giving plenty of opportunity to shape the future development of ChEMBL. Friday May 27th, Courtyard Meeting Room, EMBL-EBI, Hinxton, CB10 1SD. 9.15 Coffee/Reception 9.30 Welcome to ChUG - JPO and Brad 9.45 ChEMBL update and plans - ChEMBL group 10.45 Coffee 11.00 BeautifulBind: Prioritising targets by chemistry - Andrew Hopkins 11.45 Predicting targets using ChEMBL, and application to phospholipidosis - Rob Lowe 12.15 Lunch 13.15 QSAR workbench/Active learning - David Nicolaides 13.45 Matched-pair analysis, ChEMBL and KNIME - George Papadatos 14.15 Anti-Drugs - Willem Van Hoorn 14.45 Coffee 15.00 Comparis...

We are involved in a fascinating collaboration with Prof. Aroon Hingorani from the Clinical Epidemiology Dept of UCL Division of Medicine - working with clinical data to identify new approaches to the treatment of cardiovascular disease. Further details of the position are here . Closing date is May 23rd 2011 - so get your skates on! Behind the picture is a tale of woe....

We will be running another walkthrough of the ChEMBL database schema on Wednesday 1st June at 3pm BST (GMT+1). Please click this link to register and we'll mail you the WebEx meeting details.

Just a reminder of the first ChEMBL User Group, which will be held here on campus on Friday May 27th. Full details are on the LinkedIn group . If you are not a member, just send a join request! Attendees will each get a stick of ChEMBL rock . The agenda, with speakers, titles, etc . will be posted shortly , both here and on the LinkedIn group. The cartoon is from the eponymous xkcd

So we can run some numbers, to get an idea of the scale of the issue, and then draw things together (in the next post) with a couple of things we are thinking of ourselves to do in ChEMBL . Stereocenters For a molecule stored in a database with a single undefined sp 3 stereocenter, there are two possible distinct physical molecules (enantiomers), remember some properties are invariant w.r.t. the stereochemistry (e.g. logP) others aren't (e.g. binding energy to a receptor). As further undefined stereocenters are introduced, the number of possibilities increases as a simple combinatoric product. For three stereocenters, there are therefore 2**3 = 8 possibilities. There are a number of programs available to perform this stereo-enumeration - including stereoplex . Tautomers Enumeration of possible tautomers is a complex issue, and there has to be introduced the concept of an energy difference (which will reflect how frequent that tautomer occurs) - however the energy differenc...

There is a publication just out covering some ideas around the prioritisation and development of drug discovery strategies for infectious diseases, involving collaborators from Dundee , UPenn and IBM Almaden . RAPID is one of those recursive acronyms , just like ZINC , or GNU . Oh, and it's freely accessible, so grab a copy now! %T Rapid Analysis of Pharmacology for Infectious Diseases %J Curr.Top. Med. Chem. %V 11 %P 1292-1300 %D 2011 %A A.L. Hopkins %A G.R. Bickerton %A I.M. Carruthers %A S.K. Boyer %A H. Rubin %A J.P. Overington

I came across this interesting paper from earlier this year - " HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites ", published in FASEB J . HIV protease inhibitors were known to decrease levels of Leishmania in vivo , but the molecular target was not known. This paper shows that HIV-1 proteinase inhibitors are probably functional inhibitors of Ddi1 from Leishmania spp.  Nelfinavir (the structure above) is a 440 nM IC 50 inhibitor of L. major Ddi1 (and weaker against the human ortholog 3.3 uM). This is on the face of it, a lovely example of drug repositioning - the use of a drug for a new, and in this case, a non-obvious use. HIV-1 PR (UniProt: Q9YQ34 ) and Ddi1 (UniProt: A4H334 ) are both aspartyl proteinases (Pfam: CL0129 ), share a common mechanism, and overall architecture (although HIV-PR is a homodimer, and Ddi1 is a single chain containing two 'copies' of the HIV-PR sequence). There is a human Ddi1 ortholog as well (UniProt: Q8...

ATC code (partial): G03   On 28th April 2011, the FDA approved Abiraterone acetate (Brand name Zytiga TM , NDA 202379) for the treatment of castrate-resistant prostate cancer (CRPC). Specifically, it is indicated for use in combination with prednisone for the treatment of patients with metastatic CRPC who have received prior chemotherapy containing docetaxel. Response biomarkers are amplified Androgen Receptor (AR); PTEN loss and hormone driven ERG rearrangement. Abiraterone acetate (research code: CB-7630) is a steroid derivative with a chemical formula C26H33NO, (IUPAC: (3β)­ 17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate; SMILES= (CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H](CC=C4c5cccnc5)[C@@H]3CC=C2C1 ); InChI=1S/C26H33NO2/c1-17(28)29-20-10-12-25(2)19(15-20)6-7-21-23-9-8-22(18-5-4-14-27-16-18)26(23,3)13-11-24(21)25/h4-6,8,14,16,20-21,23-24H,7,9-13,15H2,1-3H3/t20-,21-,23-,24-,25-,26+/m0/s1). It has molecular weight 391.55 and a LogP of 5.12. Abiraterone ...