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

Friday, 30 May 2014

The results are out!



The results of the Teach-Discover-Treat (TDT) 2014 challenge were out earlier this week. TDT is an initiative to provide high quality computational chemistry tutorials that impact education and drug discovery for neglected diseases with a special focus on freely available software tools and reproducibility. 

We are very happy to announce that Rodrigo Ochoa, former summer intern in the group two years ago, won the second place (KNIME award) at the TDT challenge.

Rodrigo’s entry was based on myChEMBL (Open Innovation track) and contains several KNIME and IPython Notebook tutorials within an NTD computational research setting.  
More details here.


PS: Watch this space for an update on myChEMBL very soon. 


Team myChEMBL

Friday, 23 May 2014

Paper: An atlas of genetic influences on human blood metabolites


We got involved in the analysis of a really interesting GWAS/metabolomics study, with a publication just appearing in Nature Genetics. A link to the paper is here.

Genome-wide association scans with high-throughput metabolic profiling provide unprecedented insights into how genetic variation influences metabolism and complex disease. Here we report the most comprehensive exploration of genetic loci influencing human metabolism thus far, comprising 7,824 adult individuals from 2 European population studies. We report genome-wide significant associations at 145 metabolic loci and their biochemical connectivity with more than 400 metabolites in human blood. We extensively characterize the resulting in vivo blueprint of metabolism in human blood by integrating it with information on gene expression, heritability and overlap with known loci for complex disorders, inborn errors of metabolism and pharmacological targets. We further developed a database and web-based resources for data mining and results visualization. Our findings provide new insights into the role of inherited variation in blood metabolic diversity and identify potential new opportunities for drug development and for understanding disease.


%A Shin, So-Youn
%A Fauman, Eric B
%A Petersen, Ann-Kristin
%A Krumsiek, Jan
%A Santos, Rita
%A Huang, Jie
%A Arnold, Matthias
%A Erte, Idil
%A Forgetta, Vincenzo
%A Yang, Tsun-Po
%A Walter, Klaudia
%A Menni, Cristina
%A Chen, Lu
%A Vasquez, Louella
%A Valdes, Ana M
%A Hyde, Craig L
%A Wang, Vicky
%A Ziemek, Daniel
%A Roberts, Phoebe
%A Xi, Li
%A Grundberg, Elin
%A The Multiple Tissue Human Expression Resource (MuTHER) Consortium
%A Waldenberger, Melanie
%A Richards, J Brent
%A Mohney, Robert P
%A Milburn, Michael V
%A John, Sally L
%A Trimmer, Jeff
%A Theis, Fabian J
%A Overington, John P
%A Suhre, Karsten
%A Brosnan, M Julia
%A Gieger, Christian
%A Kastenmuller, Gabi
%A Spector, Tim D
%A Soranzo, Nicole
%T An atlas of genetic influences on human blood metabolites
%J Nat Genet
%O http://dx.doi.org/10.1038/ng.2982

Sunday, 18 May 2014

Paper: Towards predictive resistance models for agrochemicals by combining chemical and protein similarity via proteochemometric modelling


There's an Open Access opinion paper out in J. Chem. Biol. on the potential application of chemo/bio joint QSAR techniques that have historically been developed and applied to primarily human pharmaceutical applications, to the agrochemical area.

Link to the paper is here.

Later in the summer of 2014, there is some very exciting news on agrochemical data for ChEMBL!

%0 Journal Article
%D 2014
%@ 1864-6158
%J Journal of Chemical Biology
%R 10.1007/s12154-014-0112-2
%T Towards predictive resistance models for agrochemicals by combining chemical and protein similarity via proteochemometric modelling
%U http://dx.doi.org/10.1007/s12154-014-0112-2
%I Springer Berlin Heidelberg
%8 2014-05-15
%K Polypharmacology
%K Cheminformatics
%K Machine learning
%K Resistance
%A Westen, Gerard J.P.
%A Bender, Andreas
%A Overington, John P.
%P 1-5
%G English

Saturday, 17 May 2014

New Drug Approvals 2014 - Pt. VIII - Siltuximab (Sylvant™)






ATC Code:
Wikipedia:Siltuximab
ChEMBL:CHEMBL1743070

On April 23rd 2014 the FDA approved Siltuximab (Sylvant™) for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV-)-negative and human herpes virus-8 (HHV-8)-negative.

Castleman disease (Also known as giant or angiofollicular lymph node hyperplasia, lymphoid hamartoma, or angiofollicular lymph node hyperplasia) is an abnormal non-cancerous growth of the lymph node that can resemble lymphomas. It is contributed to by hyperproliferation of cytokine-producing lymphocytes. Castleman disease can be unicentric (involving a single lymph node) or multicentric (systemic). Siltuximab is approved for the multi centric disease. Overproduction of IL-6 has been linked to systemic manifestations in patients with MCD.

Siltuximab is a chimeric (human and mouse) anti-IL6 antibody. It binds human IL-6 thus preventing the interaction of IL-6 to both soluble and membrane- bound IL-6 receptors.

The target, Interleukin-6 (IL6; Uniprot = P05231; ChEMBL = CHEMBL1795129 ; canSAR = P05231)is an pro-inflammatory cytokine produced by T-lymphocytes and macrophages in response to infection or trauma.

Siltuximab is produced in Chinese hamster ovary (CHO) cells and dministered as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks. The maximum serum concentration (Cmax) was observed close to the end of infusion. At steady state, the serum mean Cmax value is 332 mcg/mL (42% CV), and the serum mean predose trough value is 84 mcg/mL (78% CV). The mean terminal half-life (t1/2) in patients after the first intravenous infusion of 11 mg/kg is 20.6 days, and clearance is 0.23 L/day (51% CV.

Sylvant™ is a product of Janssen.

The full prescribing information can be found here.

New Drug Approvals 2014 - Pt. VII - Ramucirumab (Cyramza™)





ATC Code:
Wikipedia:Ramucirumab
ChEMBL:CHEMBL1743062


On April 21, 2014 the FDA approved Ramucirumab (Cyramza™) for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy.

Gastric cancer has a very poor prognosis, with adenocarcinomas constituting ~95% of all gastric cancers (CRUK).

In a randomized, double-blind, multicenter study of ramucirumab plus best supportive care (BSC) compared with placebo plus BSC of 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]), ramucirumab improved the overall survival to a median of 5.2 months, compared to 3.8 with the placebo arm. Progression-free survival (PFS) was improved from a median of 1.3 months in the placebo arm to 2.1 months in the ramucirumab arm.

Cyramza has been issued a boxed warning because of increases in the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.




The structure of extracellular domains 2 and 3 of KDR (VEGFR2) in blue in complex with its ligand VEGFC in green. PDB=2x1x


The target of ramucirumab is the extracellular ligand-binding domain of the receptor tyrosine kinase, Vascular endothelial growth factor receptor 2 (KDR, also known as VEGFR2; Uniprot = P35968 ; ChEMBL = CHEMBL279 ;
canSAR = P35968). Ramucirumab specifically binds to KDR (VEGFR2) thus preventing the binding of its ligands VEGF-A, VEGF-C, and VEGF-D. This blockade inhibits ligand-stimulated activation of VEGF Receptor 2 and consequently, inhibits ligand-induced proliferation and migration of human endothelial cells. Elevated expression of the ligands has been shown to be clinically correlated with survival and with metastasis in gastric cancers.

Ramucirumab is administered intravenously 8 mg/kg every 2 weeks. The mean minimum concentrations (Cmin) were 50 μg/mL (6-228 μg/mL) after the third dose and 74 μg/mL (14-234 μg/mL) after the sixth dose.

Cyramza™ is a product of Eli Lilly & Co.

The full prescribing information can be found here

Thursday, 15 May 2014

ChEMBL Tour 2014 - The Netherlands, Belgium, and Luxembourg





Last year Louisa Bellis toured the UK to present on SMSdrug.net and ChEMBL. The tour was well received and a large number of people that had not heard of ChEMBL were introduced to ChEMBL.

Following the success of the previous tour, Gerard van Westen (EMBL –EBI) is going to be doing a 2014 ChEMBL tour. This year’s tour will be going to the BeNeLux. For dates and locations see below. Please feel free to attend and meet up / chat on ChEMBL, contactable via email on gerardvw [at] ebi.ac.uk

Current dates are as follows:

19th of May – Maastricht University
Host: Egon Willighagen
Time: 12.00-17.00
ChEMBL + Allosteric modulators

20th of May – Maastricht University
Host: Jos Kleinjans
Time: 09.00 - 11.30
ChEMBL + Advanced ChEMBL

20th of May – KU Leuven
Host: Pieter Annaert
Time: 14.00 -17.00
ChEMBL

21th of May – KU Leuven
Host: Piet herdewyn
Time: 09.00 -10.00
ChEMBL

21th of May – University of Luxembourg
Host: Reinhard Schneider
Time: 13.00 - 17.00
ChEMBL + Advanced ChEMBL

22nd of May – Universiteit Antwerpen
Host: Koen Augusteyns
Time: 15.00 - 17.00
ChEMBL

26th of May – VU University Amsterdam & Universiteit van Amsterdam
Hosts: Chris de Graaf & Willem Stiekema
Time: 10.00 - 15.00
ChEMBL + Allosteric modulators

28th of May – University of Groningen
Host: Alexander Domling
Time: 14.00 - 17.00
ChEMBL + Advanced ChEMBL

6th of June – Utrecht University
Host:  Roland Pieters
Time: 09.00 - 12.00
ChEMBL

6th of June – Universiteit Leiden
Host: Ad IJzerman
Time: 15.30 - 17.00
ChEMBL

17th of June – Erasmus Medical Centre, Rotterdam
Host: Roland Kanaar
Time: 14.00 - 17.00
ChEMBL

18th of June – Radboud University Nijmegen
Host: Tina Ritschel
Time: 13.30 - 15.00
ChEMBL + Allosteric modulators

Wednesday, 14 May 2014

New Drug Approvals 2014 - Pt. VI - Florbetaben F18 (Neuraceq™)




ATC Code: Unavailable
Wikipedia: Florbetaben_F18
ChEMBL: CHEMBL1908906

On March 19th the FDA approved  Florbetaben F18 (Neuraceq™) as a radioactive diagnostic agent for Positron Emission Tomography (PET) imaging of the brain to estimate β-amyloid (βA) neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease or other causes of cognitive decline.

Alzheimer's disease is the most common form of dementia, can currently not be cured and is characterised by a progressive disease pattern that usually leads to death.  Alzheimer's is predicted to affect 1 in 85 people globally by 2050.

Target(s)
Florbetaben binds with high affinity to βA in brain homogenates and selectively labels βA plaques and cerebral amyloid angiopathy. βA (PDB ; Uniprot P05067) denotes 36-43 length peptides that are believed to be crucially involved in the Alzheimer's disease mechanism. βA aggregates in the brain of Alzheimer's patients and is derived from amyloid precursor protein which is cut by certain enzymes. βA and the resulting plaques are toxic to neurons. Following intravenous administration, Florbetaben F18 crosses the blood brain barrier and shows differential retention in brain regions that contain βA deposits. Differences in signal intensity between brain regions showing specific and non­ specific Florbetaben F18 uptake form the basis for the image interpretation method.



Florbetaben F18 (CHEMBL1908906Pubchem : 53257383) is a small molecule drug with a molecular weight of 359.4 Da, an AlogP of 3.75, 12 rotatable bonds, and no rule of 5 violations. Florbetaben F18 
is administered intravenously.

Canonical SMILES: CNc1ccc(\C=C\c2ccc(OCCOCCOCCF)cc2)cc1
InChi: InChI=1S/C21H26FNO3/c1-23-20-8-4-18(5-9-20)2-3-19-6-10-21(11-7-19)26-17-16-25-15-14-24-13-12-22/h2-11,23H,12-17H2,1H3/b3-2+

Dosage
The recommended dose of Neuraceq is 300 MBq (8.1 mCi), maximum 30 mcg mass dose, administered as a single
slow intravenous bolus (6 sec/mL) in a total volume of up to 10 mL. PET images should subsequently be acquired approximately 45 - 130 minutes after injection over a period of 15-20 minutes. 

Warning / limitations of use
A positive Neuraceq scan does not establish the diagnosis of AD or any other cognitive disorder.
Safety and effectiveness of Neuraceq have not been established for:
  • Predicting development of dementia or other neurologic conditions;
  • Monitoring responses to therapies.
Neuraceq, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer.

Pharmacokinetics
Ten minutes after intravenous bolus injection of 300 MBq of Neuraceq in human volunteers, approximately 6% of the injected radioactivity was distributed to the brain. Florbetaben F 18 plasma concentrations declined by approximately 75% at 20 minutes post-injection, and by approximately 90% at 50 minutes.

Elimination
Florbetaben F18 is mainly eliminated via the hepatobiliary route with a mean half-life of approximately 1 hour. 

Metabolism
Forbetaben F18 is metabolized mainly by CYP2J2 and CYP4F2.

License holder
The license holder is Piramal Imaging, the highlights of the prescribing information can be found here.

Monday, 12 May 2014

ChEMBL funding 2014-2019.


We have recently heard that our funding application for continuation of the ChEMBL database has been successful, and going forward the resource will be funded by The Wellcome Trust and core-funding from EMBL. Below is the text from the lay description of the application. First though, we must thank you, ChEMBL users, for your support and feedback to all that we do. There is a lot of exciting future data and technology to come, and we'll post more details about what we plan to do in future blog posts. As always, we are always happy to receive visitors for tea and cake!

Drug Discovery is costly, slow and complex, and despite much fundamental scientific progress, the translation of this into new safer medicines has been slower than anticipated. One of the key steps in drug discovery is the identification of specific drug-like bioactive compounds that modulate a gene believed to be causal in the treatment of a disease. Most new drugs are themselves chemically similar to old drugs, but target new proteins, or with improved properties and distribution within the body. Understanding the activity of previous drug-like compounds is therefore key to the discovery of new drugs. However, much of the data in drug discovery is locked away in patents, publications and within companies. Our work, the ChEMBL database, builds a large database of relationships between drugs, other bioactive compounds, genes and biological function to provide a unique resource linking Genomics, Biology and Chemistry. The data we provide is all completely Open and has become an important source of data for academic, rare and neglected disease, small companies and large Pharma therapeutic discovery.

In this current application we will develop:

1) Greater coverage of bioactivity space - to deepen and formalise the data contained in ChEMBL via further curation.
2) Enhanced indexing with ontologies - to provide more structured data and ease integration with other resources.
3) Patent coverage - extend chemical-structure/target data to include the patent literature.
4) Address variation data – to include annotation of resistance and natural population variation data.
5) Technology enhancements - including RDF forms of ChEMBL and development of an API to ease data entry and curation tasks.
6) Expanded user community of ChEMBL - develop interfaces with new beneficiaries in clinical and biotechnology communities.

Wednesday, 7 May 2014

New Drug Approvals 2014 - Pt. V - Metreleptin (MyaleptTM)



ATC Code (s): A08A, A10X, A16A
Wikipedia: Metreleptin

On February 24th 2014, the FDA approved metreleptin (Tradename: Myalept), a leptin analogue, as an adjunct to diet and replacement therapy, for the treatment of complications associated with leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

Lipodystrophy is a rare condition characterized by abnormalities in adipose (fat) tissue distribution. It can be congenital, i.e. the patient is born with little or no adipose tissue, or it can be acquired, for example, after prolonged antiretroviral drug therapy some patients keep on losing adipose tissue with time. The deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance.

Leptin is an endogenous hormone, predominantly secreted in the adipose tissue, responsible to signal to the central nervous system, the status of energy stores in the body. In patients with lipodystrophy, the levels of this hormone are lower, resulting in excess caloric intake, which exacerbates the metabolic abnormalities.

Metreleptin is a recombinant human leptin analogue, which exert its function by binding to and activating the human leptin receptor. This increases insulin sensitivity and reduces food intake, soothing the metabolic abnormalities of patients with lipodystrophy.

Leptin receptor (Uniprot accession: P48357; ChEMBL ID: CHEMBL5913) is a member of the cytokine family class I, which signals through the JAK/STAT transduction pathway. Currently, there is one crystal structure of the human leptin receptor in complex with an antibody (PDBe: 3v6o). The structure is shown bellow, and the leptin receptor is depicted in green.


The -leptin USAN/INN stem covers leptin derivatives. Metreleptin is the first approved drug of its class, and the only member so far. In Japan, metreleptin was approved on May 25 th 2013 for the treatment of metabolic disorders, including lipodystrophy (see PMID: 23740412).

Metreleptin (ChEMBL: CHEMBL2107857) is a recombinant human leptin analog produced in E. coli and differs from native human leptin by the addition of a methionine residue at its amino terminus. Metreleptin is a 147-amino acid, nonglycosylated, polypeptide with one disulfide bond between Cys-97 and Cys-147 and a molecular weight of approximately 16.15 kDa.

>Metreleptin
MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLA
VYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGY
STEVVALSRLQGSLQDMLWQLDLSPGC

Metreleptin is available as a lyophilized cake, which is later reconstituted with bacteriostatic or preservative-free sterile water, for subcutaneous injection. The recommended starting daily dose is 0.06 mg/kg in patients weighting less than 40 kg, 2.5 mg in male patients weighting more than 40Kg, and 5 mg in female patients weighting more than 40 kg, with a respective maximum daily dose of 0.13 mg/kg, 10 mg and 10 mg. In healthy subjects, the peak serum concentration (Cmax) of leptin is reached at 4.0 to 4.3 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg, and following intravenous administration of metreleptin, leptin volume of distribution is 370 ± 184 mL/kg for a dose of 0.3 mg/kg/day. Metreleptin bioavailability is not influence by food intake, hence it can be administered without regard to the timing of meals.

No formal metabolism studies have been conducted with metreleptin, however, nonclinical data indicates renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. In healthy subjects, following single subcutaneous doses of 0.01 to 0.3 mg/mL, the half-life t1/2 of metreleptin is 3.8 to 4.7 hours.

Metreleptin has been approved with a black box warning due to the risks associated with the development of antimetreleptin antibodies that neutralize endogenous leptin and/or metreleptin and the risk for T-cell lymphoma. Consequently, metreleptin is only available through the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program.

The license holder for MyaleptTM is Amylin Pharmaceuticals, a subsidiary of Bristol-Myers Squibb, and the full prescribing information can be found here.