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, 23 April 2010

2010 New Drug Approvals - Pt. V - Carglumic acid (Carbaglu)




ATC code: A16AA05

On March 18th, the FDA approved carglumic acid to be marketed under the name Carbaglu as the first specific treatment for a rare form of hyperammonaemia. Carbaglu has been marketed in Europe since 2003. The ATC code is A16AA05.

Carglumic acid is used to treat a deficiency in the enzyme N-Acetyl Glutamate Synthase (NAGS), which leads to acute hyperammonaemia. NAGS deficiency is a very rare genetic disorder where a single base deletion in chromosome 17q leads to a frameshift mutation in the NAGS gene (UniProt: Q8N159) (this leads to a non-functional protein product). It is estimated that it occurs in one of ~50,000 births and due to the rareness of this autosomal recessive disorder, Carbaglu is considered as an orphan drug. NAGS deficiency manifests within the first week of life with unspecific symptoms such as failure to feed, low body temperature and sleepiness. If left untreated, the accumulation of ammonia (hyperammonemia) in the patient's blood causes lethargy, vomiting, deep coma and fatal cerebral oedema.

The catalytic product of NAGS is N-acetylglutamate, the endogenous activator of the first step in the urea cycle. Individuals with NAGS deficiency have low levels of N-acetylglutamate and the elimination of ammonia through the urea cycle is therefore impaired. Carglumic acid is a close structural analogue of N-acetylglutamate but is more stable against enzymatic hydrolysis and penetrates mitochondrial membranes more efficiently. Like N-acetylglutamate, Carglumic acid activates the urea cycle (via activating the mitochondrial protein Carbamoyl Phosphate Synthase 1 (CPS 1) (UniProt: P31327), thus keeping ammonia blood levels low.

Carglumic acid is administered orally and the daily dose is to be adjusted between 100 and 250mg/kg (for a typical 70kg adult, this corresponds to a daily dose of 7g, or ~37 mmol.day-1). The apparent Volume of distribution (Vd) is 2657L, and has a mean elimination half-life (t1/2) of 5.6 hr, and a total clearance of 5.7 L.min-1.



Carbaglu was developed by Orphan Europe and is marketed in the United States by Recordati S.p.A.
The full prescribing information for Carbaglu can be found here.
SMILES: NC(=O)N[C@H](C(=O)O)CCCC(=O)O
Molecular Formula: C7H12N2O5
Molecular Weight: 204.18058
InChI (v1.02b): InChI=1/C7H12N2O5/c8-7(14)9-4(6(12)13)2-1-3-5(10)11/h4H,1-3H2,(H,10,11)(H,12,13)(H3,8,9,14)/t4-/m0/s1
InChI Key (v1.02b): XLHYCHOTNOPCMP-BYPYZUCNBE

ChEMBL are speaking at Bio 2010

We are speaking in a session called "Open Innovation: A New Vision for Research in the Developing World" on Thursday May 6th at the 2010 BIO International Convention, in Chicago, IL.

Wednesday, 21 April 2010

Chembl_03 Released


This update contains activity data from more than 1,000 additional publications, bringing the total number of distinct compounds to 530,790 (corresponding to 640,809 compounds records) and the total number of targets to 7,330. In addition, we have carried out widespread curation of the existing chemical structures in the database. Download versions of the new database will be available on our FTP site shortly.

As always, the interface to the database is here.

Tuesday, 20 April 2010

2010 New Drug Approvals - Pt. IV - Velaglucerase Alfa (VPRIV)




ATC code: A16AB10

On 26th February, FDA has approved Velaglucerase Alfa, under the trade name VPRIV. Velaglucerase Alfa, is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease. Gaucher's disease is an autosomal recessive disorder characterized by a deficiency of the lysosomal enzyme beta-glucocerebrosidase (UniProt: P04062) (E.C. 3.2.1.45) (this enzyme is also known as glucosylceramidase, β-glucosidase, and D-glucosyl-N-acylsphingosine glucohydrolase).
Velaglucerase Alfa ATC code is A16AB10.
Glucocerebrosidase catalyses the hydrolysis of the glycolipid glucocerebroside, which is an intermediate in the glycolipid metabolism. Deficiency in this enzyme causes accumulation in the liver, spleen, bones, bone marrow and nervous system and can prevent cells and organs from working properly. Velaglucerase Alfa works by catalysing the hydrolysis of glucocerebroside, reducing the amount of accumulated glucocerebroside. Velaglucerase Alfa has the same amino acid sequence as the naturally occurring human enzyme, glucocerebrosidase. It contains 5 potential N-linked glycosylation sites, with four of these sites occupied by glycan chains. Velaglucerase Alfa is manufactured to contain predominantly high mannose-type N-linked glycan chains (and this difference in the mannose chains differentiates the very closely related drug Imiglucerase from Velagucerase alfa). These high mannose N-linked glycan chains are specifically recognized and internalised via the mannose receptor present on the surface of the cells that accumulate glucocerebroside in Gaucher disease.
>P04062|40-536
ARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRME
LSMGPIQANHTGTGLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPA
QNLLLKSYFSEEGIGYNIIRVPMASCDFSIRTYTYADTPDDFQLHNFSLP
EEDTKLKIPLIHRALQLAQRPVSLLASPWTSPTWLKTNGAVNGKGSLKGQ
PGDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGL
Several structures of glucocerebrosidase are known (an example is PDB: 1OGS)
Other similar therapies include ERT with Imiglucerase (approved in 1994 under the trade name Cerezyme) and pharmacological chaperoning, which involves the use of orally administered drugs, like for example Miglustat (approved in 2003 under the trade name Zavesca), which works by inhibiting glucocerebroside synthase. Velaglucerase Alfa is a glycoprotein of 497 amino acids, with a molecular weight of ca. 63 kDa. It has a mean half-life of 11 to 12 minutes, a mean clearance ranging from 6.72 to 7.56 mL/min/kg and a mean volume of distribution (Vd) ranging from 82 to 108 mL/kg. The recommended dosage is 60 Units/kg administrated every other week as a 60-minute intravenous infusion. The full prescribing information can be found here. Velaglucerase Alfa is manufactured by Shire Human Genetic Therapies, Inc. and the product website is www.vpriv.com.

Sunday, 18 April 2010

2nd European Chemical Biology Meeting, Prague, 20-21 May 2010

EU-OPENSCREEN are organizing the 2nd European Chemical Biology Symposium Meeting in the Czech city of Prague. It looks an excellent meeting, with some truly superb speakers. Details are at http://www.ecbs2010.eu/registration.html

Monday, 12 April 2010

New release of Kinase SARfari

New data and a slightly remodelled interface for Kinase SARfari are now available here.
Key changes are:

  • Loaded chembl_02 data - Compound count increased from 17,028 to 28,223 and Bioactivity count increased from 68,861 to 146,865
  • Compound selected sets updated - 10 Drugs compounds, previously 7, and 258 Clinical Candidates, previously 53
  • Interface updated with EMBL-EBI standard styling
  • Added Download section to interface

VEHICLe - virtual exploratory heterocyclic library

An interesting and thought provoking paper from last year was 'Heteroaromatic Rings of the Future' by Will Pitt (of UCB) (subscription required) and others at UCB. The basic idea of the paper was to exhaustively identify then analyse the class of all possible heterocycles with the following constraints. i) mono and bicyclic rings, ii) Only 5 and 6 membered rings, iii) Only containing C, N, O, S and H, iv) neutral, v) obey Hückel’s 4n+2 rule of aromaticity , and vi) Only exocyclic carbonyls. Heterocycles like this are at the very core of drug discovery and medicinal chemistry.

The dataset is now available for download from the chembl ftp site, and also as a Google document

The file contains...

  • regid: the id for each distinct ring system
  • SMILES: the encoded chemical structure of each ring system
  • Training dataset hits: the count of substructure hits found in the
    original search of commercial compound catalogues, drugs etc. (as reported in the paper).
  • Beilstein hits: the count of substructure hits in the Beilstein
    database at that time (June 2008). Some fields are blank - searching with benzene
    and other common ring systems would have taken too long.
  • Pgood: predicted synthetic tractability after training with both the
    above datasets
  • Tautomer cluster: tautomeric equivalents are grouped into clusters

Will can be contacted at will.pitt (at) ucb.com for a free reprint of the paper, or more discussions of the work.

We will integrate the VEHICLe ring system regids into Chembl at some point in the future.

%T Heteroaromatic Rings of the Future
%A W.R. Pitt
%A D.M. Parry
%A B.G. Perry
%A C.R. Groom
%J J. Med. Chem.
%D 2009
%V 52
%P 2952-2963
%O VEHICLe

Thursday, 1 April 2010

Position in Computational Biology at the Institute of Cancer Research

ChEMBL-og readers may be interested in a position at the world-leading Institute of Cancer Research in Sutton. It is for a 'Higher Scientific Officer', with the job involving primarily programming and bio/chemical data integration, the post is within the Computational Biology and Chemogenomics team.
For more information see the ICR web site.

Closing date for applications is 7th May 2010.