ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Sunday, 30 March 2014

Event: Seminar on Allosteric Drug Design, April 2014

On April 30th 2014 the University of Strathclyde will host a seminar on Allosteric Drug Design organised by the collaboration. The goal of the seminar is to bring together academic and industrial researchers with an interest in allosteric drug design and development with a view to identifying future collaborative and funding opportunities.

The seminar consists of a series of three talks by : Dr. Gerard JP van Westen (EMBL-EBI ; ChEMBL), Prof. Dr. Leonardo Scapozza (University of Geneva) and Dr. Laurent Galibert (Alpine Institute for Drug Discovery). The talks will cover various of drug design in relation to allosteric drug targets. Talks are aimed at a broad audience.

To register and for further information please go to

Thursday, 20 March 2014

New Drug Approvals 2014 - Pt. III - Droxidopa (Northera ™)

ATC Code: Unavailable
Wikipedia: Droxidopa

On February 18th the FDA approved Droxidopa (tarde name Northera™) for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic and often debilitating drop in blood pressure upon standing, and is associated with Parkinson's disease, multiple-system atrophy, and pure autonomic failure. Symptoms of NOH include dizziness, light-headedness, blurred vision, fatigue and fainting when a person stands. 

Droxidopa (also known as L-DOPS, L-threo-dihydroxyphenylserine, and SM-5688) is a prodrug which can be converted to norepinephrine (noradrenaline) by Aromatic L-amino acid decarboxylase (Uniprot P20711 ; EC Norepinephrine in turn can be converted to epinephrine by Phenylethanolamine N-methyltransferase ( Uniprot P11086 ). Droxidopa can cross the blood brain barrier, contrary to epinephrine and norepinephrine.  Patients with NOH suffer from depleted levels of epinephrine and norepinephrine. Droxidopa increases the levels of both in the peripheral nervous system and leads to an increased heart rate and blood pressure.

Droxidopa (CHEMBL2103827Pubchem : 92974 ) is a small molecule drug with a molecular weight of 213.2 Da, an AlogP of -2.92, 3 rotatable bonds, and no rule of 5 violations.

Canonical SMILES : N[C@@H]([C@H](O)c1ccc(O)c(O)c1)C(=O)O
InChi: InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1

Droxidopa starting dose is 100mg three times daily (which can be titrated to a maximum of 600 mg three times daily). One dose should be taken in late afternoon at least 3 hours prior to bedtime to reduce the potential for supine hypertension during sleep.

Neuroleptic malignant syndrome (NMS) has been reported with Droxidopa use during post-marketing surveillance in Japan. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes.

Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure
Droxidopa may exacerbate existing ischemic heart disease, arrhythmias and congestive heart failure.

Cmax of droxidopa were reached by 1 - 4 hours post-dose in healthy volunteers. High-fat meals have a moderate impact on droxidopa exposure with Cmax and AUC decreasing by 35% and 20% respectively, and delaying Cmax by approximately 2 hours.

Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL with an apparent volume of distribution of about 200 L.

The metabolism of droxidopa is mediated by catecholamine pathway and not through the cytochrome P450 system. Plasma norepinephrine levels peak within 3 to 4 hours (generally < 1 ng/mL) and variable with no consistent relationship with dose. The contribution of the metabolites of droxidopa other than norepinephrine to its pharmacological effects is not well understood.

The mean elimination half-life of droxidopa is 2.5 hours. The major route of elimination of droxidopa and its metabolites is via the kidneys.

Drug Interactions 
No dedicated drug-drug interaction studies were performed for droxidopa. Carbidopa, a peripheral dopa-decarboxylase inhibitor, could prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS).

L-DOPA/dopa-decarboxylase inhibitor combination drugs decreased clearance of droxidopa, increased AUC to droxidopa approximately 100%, and increased exposure to 3-OM-DOPS of approximately 50%. However, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events.

Dopamine agonists, amantadine derivatives, and MAO-B inhibitors do not appear to effect droxidopa clearance, no dose adjustments are required. 

Droxidopa is classified as pregnancy category C. There are no adequate and well controlled trials in pregnant women.

The license holder is Chelsea Therapeutics, the prescribing information can be found here.

Wednesday, 19 March 2014

New Drug Approvals 2013 - Pt. XXX - Umeclidinium bromide and Vilanterol (Anoro Ellipta™)

ATC codeR03AL03
WikipediaUmeclidinium bromide (and vilanterol)

ChEMBLCHEMBL1187833 (and CHEMBL1198857)

On December 18, 2013, the FDA approved Anoro Ellipta for the once-daily, long-term maintenance treatment of airflow obstruction in patients with obstructive pulmonary disease (COPD). Anoro is a combination of umeclidinium (62.5 mcg - more details below) and vilanterol inhalation powder (25 mcg - already approved in a different formulation). Ellipta is the single inhaler device:

The majority of COPD cases are due to cigarette smoking and this lung disease is a leading cause of death in the United States. Patients affected by COPD experience breathing difficulties worsening with the time as well as chronic cough and chest tightness.

Umeclidinium (also known as umeclidinium bromide, GSK573719A and GSK573719) is a small molecule with a molecular weight of 428.6 Da and AlogP of 3.34, 8 rotatable bounds and no Lipinski's rule of five violation.

Molecular formula: C29H34NO2
Canonical SMILES: OC(c1ccccc1)(c2ccccc2)C34CC[N+](CCOCc5ccccc5)(CC3)CC4
Standard InChI: InChI=1S/C29H34NO2/c31-29(26-12-6-2-7-13-26,27-14-8-3-9-15-27)28-16-19-30(20-17-28,21-18-28)22-23-32-24-25-10-4-1-5-11-25/h1-15,31H,16-24H2/q+1
Alternate form of the molecule in ChEMBL: CHEMBL523299

Mechanism of action

Anoro Ellipta relaxes the muscles located around the airways of the lung to increase the airflow in patients. This mechanism of action is mediated via umeclidinium, anticholinergic stopping muscle tightening in combination with vilanterol, a long-acting beta2-adrenergic agonist (LABA).

Safety information

The phase III trials for Anoro Ellipta included seven clinical studies, involving around 6,000 patients with COPD. The mainly reported side-effect were narrowing and obstruction of the respiratory airway (paradoxical bronchospasm), cardiovascular effects, increased pressure in the eyes (acute narrow-angle glaucoma), and worsening of urinary retention.

Note that Anoro Ellipta is not indicated for the treatment of asthma and displays a boxed warning for this indication.

Anoro Ellipta is manufactured by GlaxoSmithKline, Research Triangle Park, N.C.

Tuesday, 18 March 2014

New Drug Approvals 2014 - Pt. I Elosulfase Alfa (Vimizim™)

 ATC code: A16AB12

On February 14, 2014, the FDA approved elosulfase alfa for the treatment of Mucopolysaccharidosis Type IVA (Morquio A syndrome). Elosulfase alfa is intended to replace the missing GALNS enzyme involved in an important metabolic pathway. Absence of this enzyme leads to problems with bone development, growth and mobility.

Mucopolysaccharidoses comprise a group of lysosomal storage disorders caused by the deficiency of
specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome) is characterized by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. The sulfatase activity deficiency resultsin the accumulation of the GAG substrates, KS and C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. It is a rare autosomal recessive disease, affecting approximately 800 people in the US, and significantly shortens life expectancy, with most patients dying at an early age. Sulfonase alfa is the first approved treatment for Morquio A syndrome.

Elosulfase alfa is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors.

N-acetylgalactosamine-6-sulfatase homodimer (from PDB 4FDI)
Elosulfase alfa is a soluble glycosylated dimeric protein with two oligosaccharide chains per monomer. Each monomeric peptide chain contains 496 amino acids and has an approximate molecular mass of 55 kDa (59 kDa including the oligosaccharides). One of the oligosaccharide chains contains bis-mannose­ 6-phosphate (bisM6P). bisM6P binds a receptor at the cell surface and the binding mediates cellular uptake of the protein to the lysosome. 

Its sequence is the following:


The recommended dose is 2mg per kg given intravenously over a minimum range of 3.5 to 4.5 hours, based on infusion volume, once every week. Pre-treatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion. The mean AUC0-t at first administration is 238 min x μg/mL, but increases to 577 by week 22 of treatment, likely due to the development of neutralising antibodies. The mean elimination half-life likewise was measured as 7.52 min at first dosage, and 35.9 min at week 22 of treatment.

Elosulfase alfa comes with a boxed warning for potentially life-threatening anaphylactic reactions in some patients.

The license holder for Vimizim™is BioMarin, and the full prescribing information can be found here.

New Drug Approvals 2014 - Pt. II - Tasimelteon (HetliozTM)

ATC Code: N05CH
Wikipedia: Tasimelteon

On January 31st 2014, the FDA approved Tasimelteon (Tradename: Hetlioz; Research Code(s): VEC-162, BMS-214778), a melatonin receptor agonist, for the treatment of Non-24-hour sleep-wake disorder (Non-24).

Non-24-hour sleep–wake disorder (Non-24) is a chronic circadian rhythm sleep disorder, mostly affecting blind people. It is characterised by insomnia or excessive sleepiness related to abnormal synchronization between the 24-hour light–dark cycle and the endogenous circadian cycle (slightly longer than 24 hours). This deviation can be corrected by exposure to solar light, which resets the internal clock, however, the loss of photic input, and the absence of light perception in the majority of patients, prevents them from drifting back into normal alignment.

Tasimelteon is an agonist at melatonin MT1 and MT2 receptors, with a relative greater affinity for MT2. These receptors are thought to be involved in the control of circadian rhythms, consequently, the binding of tasimelteon to these receptors, and the resulting induced somnolence, is believed to be the mechanism by which tasimelteon aids in the synchronisation of the internal circadian clock with the 24-hour light–dark cycle.

Melatonin receptors (Uniprot accession: P48039 and P49286; ChEMBL ID: CHEMBL2094268) are members of the G-protein coupled receptor 1 family. There are no known 3D structures for these particular proteins though, however there are now several relevant homologous structures of other members of the family (see here for a current list of representative rhodopsin-like GPCR structures).

The -melteon USAN/INN stem covers selective melatonin receptor agonists. Tasimelteon is the second approved agent in this class, following the approval of Takeda's Ramelteon in 2005. Contrary to its predecessor, tasimelteon is not currently indicated to treat insomnia, and has received orphan-product designation by the FDA. Agomelatine is another member of this class, but only approved in Europe (PMID: 18673165).

Tasimelteon (IUPAC Name: N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide; Canonical smiles: CCC(=O)NC[C@@H]1C[C@H]1c2cccc3OCCc23; ChEMBL: CHEMBL2103822; PubChem: 10220503; ChemSpider: 8395995; Standard InChI Key: PTOIAAWZLUQTIO-GXFFZTMASA-N) is a synthetic small molecule , with a molecular weight of 245.3 Da, 2 hydrogen bond acceptors, 1 hydrogen bond donor, and has an ALogP of 2.2. The compound is therefore fully compliant with the rule of five.

Tasimelteon is available as oral capsules and the recommended daily dose is one single capsule of 20 mg, taken before bedtime, at the same time every night. The peak concentration (Cmax) is reached at 0.5 to 3 hours after fasted oral administration, and at steady-state in young healthy subjects, the apparent oral volume of distribution (Vd/F) is approximately 56-126 L. Tasimelteon should not be administered with food, since food decreases its bioavailability, lowering the Cmax by 44%, and delaying the Tmax by approximately 1.75 hours. At therapeutic concentrations, tasimelteon is strongly bound to plasma proteins (90%).

The primary enzymatic systems involved in the biotransformation of tasimelteon in the liver are CYP1A2 and CYP3A4. Therefore, co-administration of tasimelteon with inhibitors of CYP1A2 and CYP3A4 or inducers of CYP3A4 may significantly alter the plasma concentration of tasimelteon. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. Phenolic glucuronidation is the major phase II metabolic route. Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity is excreted in urine and approximately 4% in feces. The mean elimination half-life (t1/2) for tasimelteon is 1.3 ± 0.4 hours.

The license holder for HetliozTM is Vanda Pharmaceuticals, and the full prescribing information can be found here.

Paper: The ChEMBL database: a taster for medicinal chemists

We have just had this editorial published in Future Medicinal Chemistry. It is a high-level overview of ChEMBL, SureChEMBL and related resources, aimed primarily at medicinal chemists. The Open Access paper is here.

%T The ChEMBL database: a taster for medicinal chemists
%J Future Medicinal Chemistry
%D 2014
%O DOI:10.4155/fmc.14.8
%A G. Papadatos
%A J.P. Overington

Webinar on Drug Targets - 27th March 2014

I'm giving a webinar on Drug Targets and Drug Targeting at 2-3 pm EDT on Thursday March 27th 2014. Please note that Europe and the US have not aligned their saving times then, so the time difference will be 4 hours for the UK and Portugal (6pm GMT/WET), and 5 hours for the most of the rest of western/central Europe (7pm CET) and 6 hours for Finland and Eastern Europe (8pm EET). I plan to cover quite a lot of ground, with quite a lot of new stuff and analyses.

Registration is free on this link, and the slides will be available after the meeting on this site too. Well done ACS!!

The next in the series, on lead discovery on Thursday 24th April, is by our great friend and collaborator Tudor Oprea, so put that in your diary too.


Unpacking a GPU computation server...Leviathan unleashed

What / why?
As you might know, EMBL-EBI has a very powerful cluster. Yet some time ago we were running into some limitations and were pondering on how great it would be if we had the ability to run more concurrent threads in a single machine (avoiding the bottleneck that inevitably appears on the network for some jobs).

It turns out there is an answer, namely in the form of a GPU (graphics processing unit). This is the same type of chip that creates 3D graphics for games in your home PC / laptop. While the capabilities of individual calculation cores are relatively limited on GPUs compared to CPUs, they can have a massive amount of them in order to generate 3D environments at the speeds of 60 frames per second. Schematically it looks like this (CPU left, GPU right):

As you can see, the CPU can handle 8 threads concurrently, whereas the GPU can handle 2880 (see also this great youtube video by the myth busters). We have all kinds of ideas of calculations we want to run on the GPUs (that have shown to work well in MD), but now first ... the geek tradition that is unboxing!

The guys at Nvidia were very generous and provided us with 5 GPUs (thanks to Mark Berger and Timothy Lanfaer). Tim was also very quick with technical questions concerning the hardware specs needed and software troubleshooting. Thanks again!

At the EMBL-EBI people typically work with laptops or thin clients, and the cluster consists of blades so there was no place to put our GPUs. Yet, after a quick investigation we had a list of hardware we wanted and a big box was delivered two weeks ago !

Time to unpack...

So after opening and removing the hardware, we had a tower / 4u rackmountable chasis

Next up, placement of the GPUs inside the chassis:

Some tinkering was in order:

And finally we could boot and install the OS. We choose Ubuntu 12.04 LTS because of the stability, and availability many packages (with source code). 

Just one question remains, why 'Leviathan'? 

Given the availability of python based cuda packages, we will probably start there. Hence our server we be a very powerful incarnation of python, and what's more awe-inspiring than the Leviathan?

CUDA running
After some trouble getting the drivers to work (we use Ubuntu 12.04 LTS), Michal got everything up and running!

Potential projects
Some of the projects we will be starting with are CUDA based random forests, similarity matrix calculations, and compound clustering. If you have a good idea and would like to collaborate and co-publish, please contact us via email!

The server contains the following hardware:
Case: Supermicro GPU tower/4U server 
PSU: 1,620W Redundant PSU
CPUs: 2*Intel Xeon E5-2603 1.8GHz 4core 
RAM:  8*8GB Reg ECC DDR3 1600MHz 
Disk: 1*2TB 3.5” SATA HDD
GPUs: 1*Tesla K40; 2*Tesla K20 (one extra to be added later)

Michal & Gerard