ChEMBL Resources


Tuesday, 29 May 2012

Costs of Assays

I'm giving some talks over the summer, and am getting bored with some of the stuff I have, so I'm thinking of some new stuff to put in to add a bit of variety and interest. I'm getting interested in thinking about assay level attrition, and trying to put more of a taxonomy and inter-relationship mapping between assays used in drug discovery. As part of this, there is a cost component for each type of assay, going from very cheap to really really expensive. Here's a little picture from the presentation I've put together - I used educated guesses for the costs, so please, please critique them !

So, what do people think of the guesstimates of costs per compound per assay point on the picture above. I know it is really variable, there are startup costs to set something up, etc, etc. But what do you think about the orders of magnitude, are they about right? One of the key features of the numbers I've put there, are that there are big transitions at the switch between in silico and in vitro, and then on entering clinical trials.

The picture at the top of this post (about unicorns) is from the very funny

Monday, 14 May 2012

ChEMBL Webinar 16th May 'Schema & SQL Querying' - Posted by Louisa

This is a last call for people wanting to sign up for the "Schema & SQL Querying" webinar that will be hosted this Wednesday 16th May at 3.30pm (BST).

It will be a 45 minute webinar that will take you through the ChEMBL schema and also how to use SQL queries to extract data from the database.

Remember to register your interest in our webinars on the Doodle Poll. Make sure that you leave your **email address** as well as your name so that we can send the connection details to you. Any problems, please contact

For those of you who can't make it to this webinar, we will be hosting it again on the 27th June.

Monday, 7 May 2012

New Drug Approvals 2012 - Pt. XI - Taliglucerase alfa (ElelysoTM)

ATC code: A16AB11
Wikipedia: Taliglucerase alfa

On May 1, the FDA approved taliglucerase alfa for the treatment of Type I Gaucher's disease. Gaucher's disease is the most common of the lysosomal storage diseases. It is a hereditary disease caused by a deficiency of the enzyme β-glucocerebrosidase (Uniprot: P04062), also called β-Glucosidase. Gaucher's disease is a rare genetic disease with an incidence of 1 in 50,000 births and is considered an orphan disease. Type I Gaucher's disease is about 100 times more common in people of Ashkenazi jewish descent compared a north American population. Symptoms of type I Gaucher's disease begin typically in early adulthood and include enlarged liver and grossly enlarged spleen, impaired bone structure, anemia and low platelet levels, leading to prolonged bleeding and easy bruising. If enzyme replacement therapy (ERT) is available, the prognosis for patients with type I Gaucher's disease is good.

β-Glucocerebrosidase is an enzyme of 536 amino acids and molecular weight of approximately 59.7 kDa. The gene for β-glucocerebrosidase is located on the first chromosome (1q21) and catalyzes the hydrolyzation of glucocerebrosides (eg. ChEBI:18368), a process required for the turnover of the cellular membranes of red and white blood cells.  Macrophages clearing these cells fail to metabolize the lipids, accumulating them instead in their lysosomes.  Thus, macrophages turn into dysfunctional Gaucher cells and abnormally secrete inflammatory signals. The deficiency of glucocerebrosidase in Type I Gaucher's disease is only partial and in most cases caused by a mutation  replacing asparagine with serine in the 370th residue of the protein sequence. The deficiency of the mutant enzyme can be compensated by injection of an exogenous replacement and drastically improve the prognosis for patients with type I Gaucher disease. Prior to the approval of taliglucerase alfa, imiglucerase and velaglucerase alfa were already available ERTs for type I Gaucher's disease. The graphic below illustrates the reaction catalyzed by β-glucocerebrosidase and ERTs. The enzyme classification code for β-glucocerebrosidase is

 Taliglucerase alfa is a monomeric glycoprotein containing 4 N- linked glycosylation sites and has a molecular weight of 60,8 kDa. The recombinant enzyme differs from native human glucocerebrosidase by two amino acids at the N terminal and up to 7 amino acids at the C terminal. Taliglucerase alfa is decorated with mannose-terminated oligosaccharide chains that are specifically recognized by macrophage receptors and assist in 'homing' the enzyme to its target cells.

Taliglucerase alfa is the first ERT expressed in plant cells (carrot root cells), not mammalian cells. Cultures of plant cells are more cost-effective for the expression of recombinant enzymes. 

Crystal structure of the human glucocerebrosidase (PDBe 1ogs).

The recommended dose is 60 Units/kg of body weight administered once every 2 weeks as a 60-120 minute intravenous infusion. A Unit is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. Adverse effects include pharyngitis, headache, arthralgia, flu and back pain.

Taliglucerase alfa is marketed by Pfizer and Protalix under the brand name Elelyso

The full prescribing information can be found here.

Thursday, 3 May 2012

Deadline Approaching for Computational Drug Discovery Course

The deadline of 7th May is quickly approaching to register for the course we are hosting, here in Hinxton - "Joint EMBL-EBI and Wellcome Trust Resources for Computational Drug Discovery". This joint EBI-Wellcome Trust course aims to provide the participants with the principles of chemical biology and how to use computational methods to probe, explore and modulate biological systems using chemical tools. The course will be comprised of a mixture of lectures and hands-on components. The conceptual framework will be covered, as well as direct practical experience of retrieving and analysing chemogenomics data. Participants will be able to do their own target analysis and identify appropriate chemical tools for probing biological systems of interest to them.

Check out more details on the link, above.

Tuesday, 1 May 2012

New Drug Approvals 2012 - Pt. X - Avanafil (StendraTM)

ATC code: G04BE (partial)
Wikipedia: Avanafil

On April 27th, the FDA approved Avanafil (tradename: Stendra; Research Code: TA-1790), a phosphodiesterase 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED). ED is a sexual dysfunction characterized by the inability to produce an erection of the penis. The physiologic mechanism of penile erection involves the release of nitric oxide in the corpus cavernosum during sexual stimulation, which in turn activates the enzyme guanylate cyclase, resulting in increased levels of cyclic guanosine monophosphate (cGMP). cGMP produces relaxation of smooth muscle tissues, which in the corpus cavernosum results in vasodilation and increased blood flow. Avanafil (PubChem: CID9869929, ChemSpider: 8045620) enhances the relaxant effects of cGMP by selectively inhibiting PDE5 (ChEMBL: CHEMBL1827; Uniprot: O76074), an enzyme responsible for the degradation of cGMP.

Other PDE5 inhibitors are already available on the market and these include Sildenafil (approved in 1998; tradename: Viagra, Revatio; ChEMBL: CHEMBL192), Tadalafil (approved in 2003; tradename: Cialis; ChEMBL: CHEMBL779) and Vardenafil (approved in 2003; tradename: Levitra; ChEMBL: CHEMBL1520). These other PDE5 inhibitors are also approved for the treatment of pulmonary arterial hypertension (PAH).

PDE5 is an 875 amino acid-long enzyme (EC=, belonging to the cyclic nucleotide phosphodiesterase family (PFAM: PF00233).

>PDE5A_HUMAN cGMP-specific 3',5'-cyclic phosphodiesterase

Several crystal structures of PDE5 are now available. The catalytic domain of human PDE5 complexed with sildenafil is shown below (PDBe:1tbf)

Preclinical studies have shown that Avanafil strongly inhibits PDE5 (half maximal inhibitory concentration = 5.2 nM) in a competitive manner and is 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. Also, Avanafil has shown higher selectivity (120-fold) against PDE6 than Sildenafil (16-fold) and Vardenafil (21-fold), and high selectivity (>10 000-fold) against PDE1 compared with Sildenafil (380-fold) and Vardenafil (1000-fold). 

Avanafil has also been reported to be a faster-acting drug than Sildenafil, with an onset of action as little as 15 minutes as opposed to 30 minutes for the other drugs.

Avanafil is a synthetic small molecule, with one chiral center. Avanafil has a molecular weight of 483.95 Da, an ALogP of 2.16, 3 hydrogen bond donors and 9 hydrogen bond acceptors and thus fully rule-of-five compliant. (IUPAC: 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2S)-2-(hydroxymethyl)-pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide; Canonical Smiles: COC1=C(C=C(C=C1)CNC2=NC(=NC=C2C(=O)NCC3=NC=CC=N3)N4CCC[C@H]4CO)Cl; InChI: InChI=1S/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-

The recommended starting dose of Avanafil is 100 mg and should be taken orally as needed approximately 30 minutes before sexual activity. Depending on individual efficacy and tolerability, the dose can be varied to a maximum dose of 200 mg or decreased to 50 mg. The lowest dose that  provides efficacy should be used. The maximum recommended dosing frequency is once per day.

Avanafil is rapidly absorbed after oral administration, with a median Tmax of 30 to 45 minutes in the fasted state and 1.12 to 1.25 hours when taken with a high fat meal. Avanafil is approximately 99% bound to plasma proteins and has been found to not accumulate in plasma. It is predominantely cleared by hepatic metabolism, mainly by CYP3A4 enzyme and to a minor extent by CYP2c isoform. The plasma concentrations of the major metabolites, M4 and M16, are approximately 23% and 29% of that of the parent compound, respectively. The M4 metabolite accounts for approximately 4% of the pharmacologic activity of Avanafil, with an in vitro inhibitory potency for PDE5 of 18% of that of Avanafil. The M16 metabolite has been found inactive against PDE5. After oral administration, Avanafil is excreted as metabolites mainly in the feces (approximately 62% of administrated dose) and to a lesser extent in the urine (approximately 21% of the administrated dose). Avanafil has a terminal elimination  half-life (t1/2) of approximately 5 hours, which is comparable to that of Sildenafil (3-4h) and Vardenafil (4-5h), but very short relative to the very long half-life of Tadalafil (17.5h).

The full prescribing information of Avanafil can be found here.

The license holder is Vivus, Inc.

ChEMBL Webinar on 30th May in Japanese only

For Japanese ChEMBLers,