ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Thursday, 30 July 2009

Small Molecule Bioactivity Course At The EMBL-EBI, 25th Jan 2010

The registration for the small molecule bioactivity resources course to be held at the EMBL-EBI from Monday 25th January to Friday 29th January 2010, is now open. We will have some special guest speakers, and the aim is to make it very interactive with a focus on problem solving, so it should be good. There are a number of bursaries available so it could even be free!

Wednesday, 29 July 2009

EMBL-EBI Open Day - 3rd November 2009

There is an Open Day at the EMBL-EBI on Tuesday the 3rd November, our group will have a poster, and we may even bake some of our special cakes - a little bit like a Karelian pie (Karjalan Piirakka), but with 'angel-hair' turnip instead of a potato filling, if we have some time. Despite this offer, please check out the web link and register if you are interested in attending.

Thursday, 23 July 2009

Kinase SARfari web meeting demo - Friday 31st July

We have had quite a lot of recent interest in our Kinase SARfari chemogenomics system. Click the previous link to get an overview.

So for those interested, there will be a web meeting at Friday July 31st at 2pm (UK local time, which at this time of year is BST). Mail us for the web link and phone conference details.

Papers: Database of all (reasonable) possible molecules.

Jean-Louis Reymond's group in the Department of Chemistry and Biochemistry at the University of Berne, Switzerland have recently published a paper on their GDB-13 database. This contains all reasonable and likely stable and synthetically accessible molecules that contain up to 13 heavy atoms (restricted to the well tolerated drug like atoms of C, N, O, S and Cl) (I guess the text hackers amongst you could expand this to include F at the drop of a perl function). There are 977,468,314 molecules in GDB-13, which is as near as damn it, one billion.

To put this number in some perspective, if the same constraint on composition was applied to natural peptides, there would be only 66 possible molecules (one distinct tripeptide, 46 distinct dipeptides and 19 single amino acids). It would be interesting to push this toy analysis a little further - what fraction of available (13 atom reasonable) chemical space do natural human metabolites occupy, are there any interesting patterns, etc.?

This database is really exciting.

%A L.C. Blum
%A J.-L. Reymond
%J J. Am. Chem. Soc.
%D 2009
%V 131
%N (25)
%P 8732-8733
%O DOI:10.1021/ja902302h

Thursday, 16 July 2009

New Drug Approvals - Pt. XII - Dronedarone (Multaq)

Another drug reaching the market this year is Dronedarone (trade name Multaq), approved on July 1st. Dronedarone is a antiarrythmic agent indicated to reduce the risk of cardiovascular hospitalization in patients with a history of heart rhythm disorders. The drug is approved to be used in patients whose hearts have returned to normal rhythm or who will undergo drug or electric-shock treatment to restore a normal heart beat. Dronedarone is an antiarrythmic agent of unknown detailed mechanism of action (specifically it does not fit into one of the existing Vaughn Williams classification scheme), but is known to be a multi-channel blocker that affects calcium, potassium and sodium channels and also has anti-adrenergic receptor activity. Dronedarone (previously known by the research code SR33589) is a relatively large small molecule drug (Molecular Weight of 556.8 g.mol-1 for Dronedarone itself, and 593.2 g.mol-1 for the HCl salt), highly lipophilic and practically insoluble in water. Dronedarone has low systemic bioavailabity (~4%, increasing to ~15% if administrated with high fat meal, this low absolute oral bioavailability is due to extensive first-pass metabolism). Dronedarone has a volume of distribution of 1400L, and a high plasma protein binding of >98%. Dronedarone is extensively metabolized, mainly by CYP3A4, to the active N-debutyl metabolite and also to some inactive metabolites. The N-debutyl metabolite exhibits some pharmacologic activity but is much less potent than Dronedarone itself. Dronedarone is mostly excreted in the feces, mainly as metabolites. It has a plasma clearance of 130-150 L/hour and an elimination half-life of 13-19 hours. Recommended dosage is one tablet of 400 mg (equivalent to ca. 670 umol) twice a day, taken with morning and evening meals (see the higher bioavailability when taken with food discussed above). The full prescribing information can be found here.

Dronedarone has a boxed warning (colloquially known as 'black box').

The Dronedarone structure is N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide. It contains an aryl sulfonamide and a tertiary amine. The amine is clearly basic in nature, but aryl sulphonamides are often weak acids, and are surprisingly common in drug structures. Dronedarone is a benzofuran derivative, chemically similar to Amiodarone, a widely used and early (discovered in 1961) class III antiarrhythmic agent, whose clinical use is often limited by a multitude of side effects.

Dronedarone canonical SMILES: O=S(=O)(Nc3cc1c(oc(c1C(=O)c2ccc(OCCCN(CCCC)CCCC)cc2)CCCC)cc3)C Dronedarone InChI: InChI=1/C31H44N2O5S/c1-5-8-12-29-30(27-23-25(32-39(4,35)36)15-18- 28(27)38-29)31(34)24-13-16-26(17-14-24)37-22-11-21-33(19-9-6-2)20 -10-7-3/h13-18,23,32H,5-12,19-22H2,1-4H3 Dronedarone InChIKey: ZQTNQVWKHCQYLQ-UHFFFAOYAL Dronedarone CAS registry: 141626-36-0 Dronedarone ChemDraw: Dronedarone.cdx

The license holder for Dronedarone is Sanofi-Aventis and the product website is

Papers: The Genome of Schistosoma mansoni

There were a number of papers published today in Nature on the genome and some preliminary analysis of the pathogenic blood flukes Schistosoma mansoni and Schistosoma japonicum, these parasites are the causative agents of a variety of serious 'neglected' tropical endemic diseases - protypical of these is bilharzia (also known as snail fever, schistosomiasis or bilharziosis). Current drug treatment options are limited to Praziquantel and Oxamniquine. These blood flukes have that classic 'dual host' life-cycle initially infecting fresh water snails and then subsequently mammals - I remember seeing a diagram of this cycle in one of my first science books when I was about seven years old, and wondered how amazing and unbelievable that process was.

These genomes offer an important opportunity to identify potential sites of new therapeutic intervention. We at the EMBL-EBI contributed to the S. mansoni publication by performing a first pass 'therapeutic agent' and 'medicinal chemistry' annotation of the genome; uniquely this informatics analysis was performed essentially in 'real time' and contemporaneously with the final assembly of the complete gene set.

We will map out the general genome annotation strategy that we performed in a few future blog posts in the next week or so. More informally and extensively than could be done in the original publication.

A link to the S. mansoni paper is here (FREE MANUSCRIPT). Coverage in the broader media can be found here.

%J Nature 
%V 460
%P 352-358 
%D 16 July 2009
%O doi:10.1038/nature08160
%T The genome of the blood fluke Schistosoma mansoni
%A Matthew Berriman
%A B.J. Haas
%A P.T. LoVerde
%A R.A. Wilson
%A G.P. Dillon
%A G.C. Cerqueira
%A S.T. Mashiyama
%A B. Al-Lazikani
%A L.F. Andrade
%A P.D. Ashton
%A M.A. Aslett
%A D.C. Bartholomeu
%A G. Blandin
%A C.R. Caffrey
%A A. Coghlan
%A R. Coulson
%A T.A. Day
%A A. Delcher
%A R. DeMarco
%A A. Djikeng
%A T. Eyre
%A J.A. Gamble
%A E. Ghedin
%A Y. Gu
%A C. Hertz-Fowler
%A H. Hirai
%A Y. Hirai
%A R. Houston
%A A. Ivens
%A D.A. Johnston
%A D. Lacerda
%A C.D. Macedo
%A P. McVeigh
%A Z. Ning
%A G. Oliveira
%A J.P. Overington
%A J. Parkhill
%A M. Pertea
%A R.J. Pierce
%A A.V. Protasio
%A M.A. Quail
%A M.-A. Rajandream
%A J. Rogers
%A M. Sajid
%A S.L. Salzberg
%A M. Stanke
%A A.R. Tivey
%A O. White
%A D.L. Williams
%A J. Wortman
%A W. Wu
%A M. Zamania
%A A. Zerlotini
%A C.M. Fraser-Liggett
%A B.G. Barrell
%A N.M. El-Sayed

Wednesday, 15 July 2009

New Drug Approvals - Pt. XI - Prasugrel Hydrochloride (Effient)

The latest approval this year is Prasugrel (USAN), approved on July 10th under the trade name Effient. Prasugrel is a P2Y12 receptor platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention. Prasugrel is the third to market in the thienopyridine class of ADP receptors antagonists, after Ticlopidine (trade name Ticlid) and Clopidogrel (trade name Plavix). Prasugrel is a prodrug; meaning that Prasugrel is not therapeutically active itself, but is metabolized in the body to give the pharmacologically active metabolite. Additionally, the metabolically activated form of Prasugrel irreversibly binds to its receptor - this means that it forms an unbreakable chemical bond to its target, again this is quite an unusual feature.

Prasugrel is a small molecule drug (Molecular Weight of 343.4 g.mol-1 for Prasugrel itself and 409.9 g.mol-1 for the HCl salt), is fully Rule-of-Five compliant, lipophilic and insoluble in water. Prasugrel has a good oral absorption (≥79% absorbed), an elimination half-life of ~7 hours (for the active metabolite, see below) and a high plasma protein binding of 98%. The activation of Prasugrel is rapid and complex, being first metabolized first to a thiolactone, which is then converted to the active metabolite, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. CYP2B6 is quite an unusual cytochrome p450 to be involved in drug metabolism. Prasugrel's active metabolite has an apparent volume of distribution of 44-68 L and an apparent clearance of 112-166 L/h. Prasugrel's excretion is mostly renal (68%), being excreted as inactive metabolites. Recommended dosage is initially a 60 mg once a day 'loading dose', continuing at 10 mg once daily, in combination with 75-325 mg of aspirin. Full prescribing information can be found here.

Prasugrel has a boxed warning (colloquially know as 'black box').

The chemical structure is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. The molecule contains a piperidine ring fused with a thiophene ring (the common feature between to the thienopyridine class of ADP receptors). It also contains a racemic center adjacent to the piperidine nitrogen. Since the drug is racemic, the stereoisomers have different pharmacological activity and different metabolic properties. The remainder of the molecule is quite rigid, with few rotational bonds.

Prasugrel canonical SMILES: Fc1ccccc1C(N3Cc2c(sc(OC(=O)C)c2)CC3)C(=O)C4CC4 Prasugrel InChI: InChI=1/C20H20FNO3S/c1-12(23)25-18-10-14-11-22(9-8-17(14)26-18)19 (20(24)13-6-7-13)15-4-2-3-5-16(15)21/h2-5,10,13,19H,6-9,11H2,1H3 Prasugrel InChIKey: DTGLZDAWLRGWQN-UHFFFAOYAR Prasugrel CAS registry: 150322-43-3 Prasugrel ChemDraw: Prasugrel.cdx

The product is marketed by Eli Lilly and Company and Daiichi Sankyo, Inc. and manufactured by Eli Lilly and Company. The product website is

New Drug Approvals - Pt. X - Benzyl Alcohol (Ulesfia)

Also approved this year is Benzyl Alcohol, under the trade name Ulesfia, approved on April 9th. Benzyl Alcohol has many uses, but it is now approved as a pediculicide, indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Benzyl Alcohol inhibits lice from closing their respiratory spiracles, causing the lice to asphyxiate. This is the first and only prescription medication that kills head lice by asphyxiation without potential neurotoxic side effects. Ulesfia is supplied as a topical lotion containing Benzyl Alcohol, 5%. Benzyl Alcohol is a small molecule drug (Molecular Weight of 108.1 g.mol-1), fully Rule-of-Five compliant, slightly lipophilic and partially soluble in water. Recommended administration and full prescribing information can be found here.

The chemical structure is very simple, and probably does not warrant much useful disection and discussion.

Benzyl Alcohol canonical SMILES: OCc1ccccc1 Benzyl Alcohol InChI: InChI=1/C7H8O/c8-6-7-4-2-1-3-5-7/h1-5,8H,6H2 Benzyl Alcohol InChIKey: WVDDGKGOMKODPV-UHFFFAOYAH Benzyl Alcohol CAS registry: 100-51-6 Benzyl Alcohol ChemDraw: Benzyl Alcohol.cdx

The license holder is Sciele Pharma, Inc. and the product website is

Monday, 13 July 2009

Conference: Toxicogenomics, Seoul, September 20-23rd 2009

Here are some details of an interesting conference on Toxicogenomics this September in South Korea. Toxicology is arguably one of the last great frontiers of multi-omics data, with undoubtedly the largest potential impact on human health and the broader biosystem. One of the highly attractive informatics aspects of toxicology type data is the pure complexity of it all, small molecules, known and potential metabolites of these, gene transcript response, proteomics, secondary pharmacology, model organism differences, pathways, human variation, benefit vs. risk, etc.

The conference website is here

Monday, 6 July 2009

Course: Small Molecule Bioactivity Resources at the EMBL-EBI

Sorry for not having posted for so long, but some good news. There will be a residential course held at the EMBL-EBI from Monday 25th January to Friday 29th January 2010, the agenda will focus on applications of SAR databases to biological problems, but of course we'll also include contributions from many other faculty at the EMBL-EBI to illustrate how 'it all fits togther'. We hope to have eight full bursaries available for the course, and registration will open at the end of this July. I'll post further details on the chembl-og when there is more available.....

New Drug Approvals - Pt. IX - Besifloxacin (Besivance)

Also on the market this year is Besifloxacin Hydrochloride (USAN) which is marketed as Besivance, approved on May 28th. Besifloxacin is a fluoroquinolone antimicrobial indicated for the treatment of bacterial conjunctivitis, and competes against other fluoroquinolones for the ophthalmic treatment of bacterial infections. Besifloxacin has activity against Gram-positive and Gram-negative bacteria and acts through inhibition of both bacterial DNA gyrase and topoisomerase IV. Besifloxacin is known to be active against various Corynebacterium, Haemophilus, Moraxella, Staphylococcus and Streptococcus spp. Besifloxacin is a small molecule drug (Molecular Weight of 393.8 g.mol-1 for Besifloxacin itself, and 430.3 g.mol-1 for the HCl salt), is Rule-of-Five compliant and is delivered as an ophthalmic suspension. Besifloxacin has a plasma half-life is of 7 hours. Recommended dosage is one drop instilled in the affected eye(s) 3 times a day, four to twelve hours apart, for 7 days. The full prescribing information is here.

The structure (+)-7[(3R)-3-aminohexahydro-1H-azepin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) contains both an amine and a carboxylic acid functional group, and so will normally exist as a zwitterion. Overall, Besifloxacin is a rigid molecule with few rotatable bonds. The fluoroquinolone class of antibiotics is quite extensive, and is named after the fluro-substituted, fused six-six ring structure at the center of the molecule containing a nitrogen and also the aryl-ketone (the 'one' part of the name).

Besifloxacin Canonical SMILES: N[C@@H]4CCCCN(c3c(F)cc2c(=O)c(C(=O)O)cn(C1CC1)c2c3Cl)C4 Besifloxacin InChI: InChI=1S/C19H21ClFN3O3/c20-15-16-12(18(25)13(19(26)27)9-24(16)11-4-5-11)7-14(21)17(15)23-6-2-1-3-10(22)8-23/h7,9-11H,1-6,8,22H2,(H,26,27) Besifloxacin InChIKey: QFFGVLORLPOAEC-UHFFFAOYSA-N Besifloxacin CAS registry: 141388-76-3 Besifloxacin ChemDraw: Besifloxacin.cdx

The manufacturer of Besifloxacin is Bausch & Lomb, Inc. and the product website is

New Drug Approvals - Pt. VIII - Iloperidone (Fanapt)

Another drug onto the market this year is Iloperidone (USAN) marketed as Fanapt, which was approved on May 6th. Iloperidone is an antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone displays broad polypharmacology, acting as an antagonist at dopamine D2 (Ki of 6.3 nM) and dopamine D3 (Ki of 7.1 nM), serotonin 5-HT2A (Ki of 5.6 nM), dopamine D4 (Ki 25 nM), 5HT6 (Ki of 43 nM), 5HT7 (Ki of 22 nM) and alpha-1 adrenergic receptor (Ki of 36nM) (phew!) and belongs to the general class of atypical antipsychotics. Lower affinities, but also probably relavent for the clinical pharmacology, are observed at the 5HT1A, D1 and H1 receptors). Iloperidone is a small molecule drug (Molecular Weight of 426.5 g.mol-1), is fully Rule-of-Five compliant, lipophilic and pratically insoluble in water and has good oral absorption (96% bioavailable). Iloperidone has a plasma half-life of 18 hours, a volume of distribution of 1,340-2,800L and plasma protein binding of ~95%.

Iloperidone elimination is mainly through CYP dependent hepatic metabolism (specifically CYP3A4 and CYP2D6); some of these metabolites are themselves pharmacologically active. CYP2D6 is an example of a genetically variable gene, with a fraction of the population having a form of the gene that is significantly less active - so called 'slow metabolizers', this generally leads to variability of drug response. Iloperidone has an apparent clearance of 47-102 L/hour, with the bulk of the clearance being renal (i.e.. the drug is excreted in the urine). The recommended dosage is 12 to 24 mg/day administrated twice daily (equivalent to ca. 28-56uM). Like many drugs of this class, there are a broad range of potential adverse events, including a propensity for the compound to increase QTc interval. The full prescribing information can be found here.

Iloperidone has a boxed warning (colloquially known as a 'black box').

Iloperidone belongs to the chemical class of piperidinyl-benzisoxazole derivatives - the piperidine in the six membered ring containing the nitrogen in the middle of the molecule, while the benzisoxazole is the fused five-six dual ring structure at the bottom left. Its structure 4'-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone contains a tertiary amine which makes the molecule basic, but otherwise the molecule is largely lipophilic in character. A relatively unusual chemical feature for a drug is the presence of the aryl-ketone group.

Iloperidone canonical SMILES: O=C(c4ccc(OCCCN3CCC(c2noc1cc(F)ccc12)CC3)c(OC)c4)C Iloperidone InChI: InChI=1/C24H27FN2O4/c1-16(28)18-4-7-21(23(14-18)29-2)30-13-3-10-2 7-11-8-17(9-12-27)24-20-6-5-19(25)15-22(20)31-26-24/h4-7,14-15,17 H,3,8-13H2,1-2H3 Iloperidone InChIKey: XMXHEBAFVSFQEX-UHFFFAOYAT Iloperidone CAS registry: 133454-47-4 Iloperidone ChemDraw: Iloperidone.cdx

The license holder for Iloperidone is Vanda Pharmaceuticals and the product website is