ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Sunday, 30 January 2011

The ChEMBL Group, Staff and Funding (Jan 2011)

I've put together some slides for an internal meeting, and I thought they may be interesting to the wider world, maybe.

The ChEMBL group currently has fifteen staff located at the EMBL-EBI. We perform both 'Service' and 'Research' work within the group, with the distribution plotted below. The total service resourcing is 9.8 people (65% of staff), with the majority directed towards development and support of the various  ChEMBL resources. (All numbers refer to number of staff positions)

The breakdown of funding sources for the group are as follows. 


New Drug Approvals 2011 - Pt. III Ioflupane 123I (DaTSCANTM)

ATC code : V09AB03

On January 14th 2011, the FDA approved Ioflupane 123I (USAN: Ioflupane I123 USAN date: 2009 tradename: DaTSCAN, NDA 022454)) for the imaging of dopamine transporters in the brain of adult patients with potential Parkinsonian Syndromes. Ioflupane is a radiopharmaceutical agent intended for use with single photon emission computed tomography (SPECT) imaging, to help physicians differentiate essential tremor, from tremor due to Parkinsonian Syndromes.

Ioflupane 123I binds to, and allows imaging of, the Dopamine Transporter (DaT) (Ki = 0.62 nM IC50 = 0.71 nM). Synonym:SLC6A3 UniProt:Q01959 Pfam:PF00209). Variation or malfunction of the Dopamine Transporter is linked to many neurological and psychiatric disorders.
The chemical structure of Ioflupane (IUPAC: methyl(1S,3S,4S,5R)-8-(3-fluoropropyl)-3-(4-iodanylphenyl)-8-azabicyclo[3.2.1]octane-4-carboxylate PubChem: CID3086674) is a tropane derivative; tropanes are a class of natural product alkaloids found in a large number of plant species, notable members of this chemical class include cocaine and atropine (a.k.a. hyoscyamine). Therefore Ioflupane is a natural product derivative. The molecular weight is 427.3 Da, with a relatively large fraction of that coming from the single iodine atom (126.9 Da for 'normal' iodine). The calculated logP is 4.0 and Ioflupane contains no hydrogen bond donors and six hydrogen bond acceptors. Ioflupane is therefore fully compliant with Lipinski's rule of five. Other relevant molecular descriptors include a polar surface area of 29.5 Å2 and the molecule contains 6 rotatable bonds. The iodine in DaTSCAN is the radioactive isotope 123I, which has a half-life of 13.2 hr, and decays with emission of gamma rays, it is these gamma rays that are imaged, showing the location of the DaTs in the brain.

Ioflupane 123I is dosed intravenously, with a total recommended dose in the range 111 to 185 MBq.

Ioflupane (123I) is cleared from the blood after intravenous (iv) injection, with only 5% of the administered activity remaining in whole blood  5 minutes post-administration. Uptake in the brain is rapid, reaching about 7% of injected activity 10 minutes post-administration, then decreasing to ~3% after 5 hours. By 48 hours post-injection, ~60% of the injected radioactivity is excreted in the urine, with faecal excretion calculated at ~14%.

The license holder for DaTSCAN is GE Healthcare, the product website is here, and the full prescribing information can be found here (DaTSCAN was approved in the EU in 2007, the European SPC can be found here).

Thursday, 27 January 2011

New Drug Approvals 2011 - Pt. II Vilazodone hydrochloride (ViibrydTM)

ATC code (partial): N06A

On January 21st 2011, the FDA approved Vilazodone hydrochloride for the treatment of major depressive disorder (MDD) (research code: EMD-68843, tradename:Viibryd) (NDA 022567). MDD is a mental disorder believed to arise from abnormal levels of neurotransmitters (primarily serotonin) in the central nervous system. Symptoms are of broad spectrum and typically include depressed mood, fatigue, change of appetite and weight and suicidal thoughts, or attempted suicide. There are already a large number of therapeutics available for the treatment of MDD including the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (ChEMBL41), sertraline (ChEMBL809), paroxetine (CHEMBL569172) and more recently escitalopram (CHEMBL1508). A number of other mechanisms have been explored for treatment of depression, including drugs such as against the serotonin receptor 5HT1A - such as buspirone (research code:BMS-528215, tradename:BuSpar)CHEMBL49) and flesinoxan (clinical trial phase only). Vilazodone however is the first SSRI that also is a partial agonist of 5TH1A (and as such show designed and intended polypharmacology).

Brain function relies on the transmission and regulation of excitatory and inhibitory signals at the synapses of nerve cells. Upon activation, a presynaptic neuron releases neurotransmitters into the synaptic cleft which in turn activate or inhibit the postsynaptic neuron by binding specific receptors. One of the neurotransmitters with excitatory effects is the biogenic amine serotonin (CHEMBL39, CHEBI:28790). After its release from the presynaptic neuron, Serotonin transmits an excitatory signal and is then removed from the synaptic cleft by an uptake mechanism involving the sodium dependent serotonin transporter (SERT) (Ki 0.1nM Uniprot:P31645 Pfam:PF00209). SERT is a member of a very important family of drug targets including the analogous norepinephrine transporter, other pharmacologically important ligands that have related transporters include GABA, dopamine, amino-acids and so forth) Vilazodone is selective for serotonin over the norepinephrine (Ki 56 nM UniProt:P23975) and dopamine transporters (Ki 37 nM UniProt:Q01959). Inhibition of serotonin reuptake with SSRIs leads to increased levels of serotonin in the synaptic cleft and is used in the treatment of MDD to compensate for the lower homeostatic levels of serotonin in MDD patients compared to healthy individuals. The exact mechanism by which this helps MDD patients is not clear but involves long-term desensitization of presynaptic serotonin receptors which are part of a negative feedback loop in the biosynthesis of serotonin. In addition to it's effects as an SSRI, Vilazodone is a partial agonist of the 5HT1A receptor (IC50 2.1 nM, Uniprot:P08908, Pfam:PF00001, ChEMBL:214) (and selective over the related 5-HT1D, 5-HT2A, and 5-HT2C receptors). However the net result of this partial action on serotonergic transmission and its role in Vilazodone’s overall antidepressant effect are unclear. The 5HT1A receptor is a rhodopsin-like G-protein-coupled receptor (GPCR), the largest single family of historically successful drug targets.

Vilazodone (IUPAC: 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide
InChI: 1S/C26H27N5O2/c27-16-18-4-6-23-22(13-18)19(17-29-23)3-1-2-8-30-9-11-31(12-10-30)21-5-7-24-20(14-21)15-25(33-24)26(28)32/h4-7,13-15,17,29H,1-3,8-12H2,(H2,28,32)
SMILES: NC(=O)c1oc2ccc(cc2c1)N3CCN(CCCCc4c[nH]c5ccc(cc45)C#N)CC3 ChemSpider: 5293518 Chembl:439849) is a synthetic organic molecule with no chiral centers and a molecular weight of 441.5 Da (for the free base) and a calculated LogP of 4.54. With 7 hydrogen bond acceptors and two hydrogen bond donors it is therefore fully compliant with the Lipinski Rule of five. The 7 rotatable bonds make Vilazodone a rather flexible compound. The physical chemistry will be dominated by the basic center in the piperazine ring.

The pharmacology of Vilazodone is largely due to the parent, dosed drug, and due to the long terminal half life of 25 hr (elimination is largely hepatic), steady state plasma levels are reached after about three days. The mean Cmax value is 156 ng/mL, and the mean AUC (0-24 hours) value is 1645 ng·h/mL. Tmax is around 4.5 hr post administration. Vilazodone is widely distributed and approximately 96-99% protein-bound. Vilazodone is extensively metabolized in the liver through CYP and non-CYP pathways with major contributions from CYP3A4 (Uniprot Id: P08684). The non-CYP route is believed to open via liver carboxylesterase (Uniprot Id: P23141). The absolute bioavailability of vilazodone is 72% with food - Vilazodone shows a large food effect, and if taken without food, bioavailability is significantly lower.

Vilazodone is administered orally at a typical dose of 40 mg once daily (equivalent to a daily dose of ~83.6 uM of Vilazodone). At start of therapy, the drug is titrated, starting with 10mg once daily over the course of seven days followed by 20 mg once daily over another 7 days before the full dose of 45 mg per day is administered.

Many drugs of this general class have inherent safety issues, and Vilazodone has safety risks associated with the induction of suicidal thoughts in young adults, adolescents and children. Vilazodone is not approved for the treatment of depressive disorders in children. Viibryd has a boxed warning.

The full prescribing information is found for Vilazodone here.

The license holder is Clinical Data and the product website is

Wednesday, 26 January 2011

ChEMBL visit New York March 2011

Some of us are travelling to New York on business the week of 21st March 2011. We have some space in our schedule for portions of Tuesday the 22nd and Wednesday the 23rd, so if there is interest in meeting up for a coffee, a small seminar on ChEMBL, some training, etc., let me know. We'll probably stay somewhere on the upper East Side, but would be happy to travel to you to meet up.

Friday, 21 January 2011

2011 EIPOD Fellowships with ChEMBL

EMBL run a vibrant postdoctoral fellowship programme called EIPOD. This funds interdisciplinary projects between research groups within EMBL. The 2011 appointment process is just starting, and we are pleased to announce that the ChEMBL group is involved in two projects this year - both based around using informatics techniques to improve Drug Discovery. EIPOD projects have multiple supervisors, with one lab acting as the lead and primary host for the postdoc. Projects are either selected from an approved list, or the candidate can develop their own interdisciplinary project following consultation with the relevant group leaders.

The first project is part of our interest in mining the Internet for clinical development candidate data, delivering an open resource for data-mining and also to lower barriers to data sharing and collaboration. This EIPOD addresses part of this broader project (a sort of ‘Open Source Competitive Intelligence Resource for Drug Discovery’), and specifically looks to identify, define and annotate newly disclosed/published clinical candidates from non-patent and non-literature sources. The project will be led by the text-mining and literature groups here at the EBI under Dietrich Rebholz-Schuhmann and Johanna McEntyre. Details of the project are here.

The second project is connected with using next generation sequencing (NGS) techniques to profile the organisms present in natural product screening collections and environmentally derived samples. We will attempt to develop a series of heuristics and a combined experimental and informatics pipeline to identify ‘interesting’ samples. Interesting here means those likely to contain chemically novel natural products, with an aim to use these as a source of new leads for drug discovery. This project will be based in the ChEMBL group, and will involve collaboration with the Hunter (EBI) and Bork (Heidelberg) groups. Details of the project are here.

Further details of the application process and deadlines can be found here, and if you are interested in discussing either of the projects (or would be interested in developing your own project idea involving the ChEMBL group), please feel free to mail us.

There are also several other excellent Chemical Biology EIPOD projects available in other labs at EMBL.

Thursday, 20 January 2011

New Drug Approvals 2011 - Pt. I Spinosad (NatrobaTM)

partial ATC code: P03A

The first FDA new drug approval of 2011 is Spinosad, approved on Jan 18th 2011 (NDA 022408). Spinosad (tradename: Natroba) is a pediculicide, indicated for the topical treatment of head lice (the parasitic insect Pediculus humanus capitis) infestations in patients aged over four years of. One gram of Natroba contains 9 mg of Spinosad as a viscous suspension.

Spinosad has a unique mode of action that is different from all other known pediculicides. Spinosad causes excitation of the insect nervous system, leading to involuntary muscle contractions, prostration tremors and finally paralysis and death. These effects are similar to those associated with the activation of nicotinic acetylcholine receptors (nAChRs), and there is evidence that insect nAChRs are involved in the mechanism of action of spinosyn A and D (two active components of Spinosad) a representative nAChR for a target species is Drosophila melanogaster nAChR Dalpha6 (UniProt:Q86MN8).  nAChRs are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction. These receptors are triggered by the binding of the neurotransmitter acetylcholine and their stimulation causes muscular contraction. This protein family is structurally related to the significant family of human drug targets - the ligand-gated ion channels, in which drugs bind at extracellular sites in the so-called ligand-binding domain (Pfam:PF02931).

Spinosad has already been used for a number of years as an oral anti-flea medication for pets and also to control a variety of insect pests, such as fruit flies, caterpillars, spider mites, fire ants; and has now received approval as a prescription human medication. Since it does not significantly affect beneficial insects and predatory mites, Spinosad is actually recommended for use in an integrated pest management program for commercial greenhouses. Spinosad is the first head lice treatment that does not require combing and it has been shown to be more effective in eliminating head lice than previously approved treatments. These include both natural and synthetic products, such as Malathion 0.5% (tradename: Ovide), Permethrin 1% (tradename: Nix), Pyrethrins (tradename: Rid) and the recently approved Benzyl Alcohol 5% (tradename: Ulesfia; approved in 2009). 

Spinosad, the active ingredient, is derived from the fermentation of a naturally occurring soil dwelling bacterium called Saccharopolyspora spinosa, a rare actinomycete collected on a Caribean island in 1982. Spinosad is a mixture of the natural products spinosyn A and spinosyn D in a ratio of approximately 5 to 1.

Spinosyn A (IUPAC: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-13-{[(2R,5S,6R)-5- (dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-methyl-7,15-dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl 6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranoside; INCHIKEY: SRJQTHAZUNRMPR-UYQKXTDMBW; SMILES: [H][C@@]12C[C@H](C[C@@]1([H])[C@]1([H])C=C3C(=O)[C@H](C)[C@H](CCC[C@H](CC)OC(=O)C[C@@]3([H])[C@]1([H])C=C2)O[C@H]1CC[C@@H]([C@@H](C)O1)N(C)C)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC; ChEMBL: CHEMBL501411; ChEBI: CHEBI:9230; PubChem: CID115003; ChemSpider: 391358) has a molecular weight of 731.96 Da, no hydrogen bond donors, eleven hydrogen bond acceptors, a calculated logP of 4.9 and a polar surface area of 111 Å2. Spinosyn D differs from Spinosyn A, having one more methyl group at the double bond carbon of the cyclohexene of the indacene derived central moiety. Thus, Spinosyn D (IUPAC: (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-{[(2R,5S,6R)-5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-dimethyl-7,15-dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl 6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranoside; INCHIKEY: RDECBWLKMPEKPM-PSCJHHPTBK; SMILES: [H][C@@]12C[C@H](C[C@@]1([H])[C@]1([H])C=C3C(=O)[C@H](C)[C@H](CCC[C@H](CC)OC(=O)C[C@@]3([H])[C@]1([H])C=C2C)O[C@H]1CC[C@@H]([C@@H](C)O1)N(C)C)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC; ChEMBL: CHEMBL503450; ChEBI: CHEBI:9232; PubChem: CID183094; ChemSpider: 159214) has a molecular weight of 745.98 Da, and, like Spinosyn A, has no hydrogen bond donors, eleven hydrogen bond acceptors, a calculated logP of 4.8 and a polar surface area of 111 Å2. Both Spinosyn A and B fail the rule of five. A notable feature of both spinosyn structures is the tertiary amine, which will be protonated under physiological conditions and the relatively small macrolide (in this case a 12-membered cyclic lactone) ring fused to the rigid and lipophilic 5:6:5 ring system. Many natural products contain a macrolide ring.

The full US prescribing information can be found here. The license holder is ParaPRO LLC and the product website is