ChEMBL

There are clearly some advantages in pooling or analysing website search data - it highlights interesting trends, something becoming more interesting to a user community can spot emerging events, etc. It can alert to flu outbreaks (there was a Science paper from google on this, don't have the reference handy though - you may be able to find it with google though.....). There is a huge interest in many sites that I use in tracking and analysing query terms and usage patterns, and in some contexts this is just the thing to do - like when ebay teases me (and surely of all the tortured obsessive souls on the planet, it is just me and me alone) with a rare phosphor or perforation machin variant I don't have.

The types of query that people perform can clearly also be used to develop ways of improving a website, or specifically the performance of search queries - and for algorithm development this information can be like gold-dust. There are now many chemical fingerprint systems available, and adapting the features/structures of these to typical user queries is really valuable in their development.

There are essentially two distinct aspects to user's expectations/rights of privacy when using a website like ChEMBL.

• There is a personal privacy issue - 'why is John Overington interested in compounds for the treatment of obesity?'. This is an primarily an embarrassment sort of thing ('hey, is this guy a bit chubby?'), or maybe a commercially sensitive thing ('he's interested in obesity stuff; heh, let's raise the price for him', or 'let's show him some adverts for chips', or 'let's contact his rival and let them know he's interested in his weight'). These latter things are behind the feature where you first search for a flight and the price is great, then the next time you look, it's gone up - allegedly.
• There's a more fundamental IP issue though -  The simple disclosure of a search term can be commercially damaging, and potentially stop the development of life-saving therapies. The simplest case is chemical structure and drug patents. The most important patent claim in drug discovery is to have composition of matter (and don't get all hissy over pharma misusing the patent system, since patents are absolutely essential for the development of new medicines, the treatment of disease, improvement of food supplies, for funding future R&D, for a source of employment, license revenues to Universities, and taxation revenues, etc). This composition of matter is a claim of a novel chemical structure, that no-one has disclosed before, and it is useful for something. If the structure is not novel, then the patent can be readily invalidated.

On September 12^th the FDA approved Teriflunomide (tradename AUBAGIO, ChEMBL973), an orally administered drug for the treatment of relapsing forms of Multiple Sclerosis (MS). Teriflunomide is an inhibitor of of pyrimidine synthesis by dihydroorotate dehydrogenase (DHODH, Uniprot: Q02127) but is it not certain if this explains the effect of the drug on MS lesions. Teriflunomide inhibits rapidly dividing cells, which includes activated T lymphocytes thought to drive the MS disease process. The net effect of the inhibition of DHODH is that lymphocytes cannot accumulate sufficient pyrimidines for DNA synthesis. Additionally, Teriflunomide has been shown to inhibit the activation of nuclear factor kappaB and tyrosine kinases, but at doses higher than needed for the observed anti-inflammatory effects. Teriflunomide is the active metabolite of an already approved drug Leflunomide (tradename Arava, ChEMBL960) indicated for the treatment of rheumatoid and psoriatic arthritis.

MS is an inflammatory disease characterised by damaging of the myelin sheaths surrounding the axons of the brain and spinal cord. This demyelation results in a broad number of symptoms scarring. The prevalence ranges between 2 – 150 per 100.000 and the disease onset usually occurs in young adults. MS cannot currently be cured and the prognosis is difficult to predict, depending on the subtype of the disease. The United States National Multiple Sclerosis Society characterised four clinical courses, two of which are classified as relapsing forms of MS namely 'relapsing remitting' and 'progressive relapsing'.

Currently there are six other disease-modifying treatments for MS approved by regulatory agencies. These are: Fingolimod (trade name Gilenya, CHEMBL314854), interferon beta-1a (trade names Avonex, CinnoVex, ReciGen and Rebif, CHEMBL1201562) and interferon beta-1b (U.S. trade name Betaseron, in Europe and Japan Betaferon, CHEMBL1201563), glatiramer acetate (trade name Copaxone, CHEMBL1201507), mitoxantrone (trade name Novantrone, CHEMBL58) and natalizumab (trade name Tysabri). Of these drugs, only Fingolimod is orally administered, the others are injected intravenously or subcutaneously, hence Terfiflunomide is the second oral treatment option for MS.




Terfiflunomide is a small molecule drug with a molecular mass of 270.20 g/ml, an AlogP of 2.09 , 3 rotatable bonds and does not violate the rule of 5.
 Canonical SMILES : C\C(=C(/C#N)\C(=O)Nc1ccc(cc1)C(F)(F)F)\O
 InChi: InChI=1S/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,18H,1H3,(H,17,19)/b10-7-

The structure of the drug can interconvert between Z and E stereoisomers with the Z enol being the most stable and the active form.

DHODH (EC: 1.3.5.2, Uniprot: Q02127, PDB: 1D3G, CHEMBL: ChEMBL1966, IntAct: EBI-3928775 ), is a 395 amino acid monomer located at the mitochondrion inner membrane. The protein is a single-pass membrane protein with the catalytic site located in the mitochondrial inter-membrane space.


The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.

The median time to reach maximum plasma concentrations is between 1 and 4 hours post-dose following and oral administration. The half life is approximately 18-19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations.

Teriflunomide is mainly eliminated through direct biliary excretion of unchanged drug and renal excretion of metabolites.

The drug comes with a box warning to alert prescribers to the risk of liver problems, including death, and a risk of birth defects. Physicians are advised to do a blood test for liver function prior to prescribing Terfiflunomide and periodically during the course of treatment. Based on animal studies, the drug may cause fetal harm.

The license holder is the Genzyme Corporation and the full prescribing information can be found here.

• Retrieval of compounds by Canonical SMILES string using HTTP POST *.
• Retrieval of compounds containing a particular substructure, as given by a Canonical SMILES string using HTTP POST *.
• Retrieval of a list of compounds similar, at a given cutoff percentage Tanimoto similarity, to one represented by a given Canonical SMILES string using HTTP POST *.
• Retrieval of larger compound images, as given by a compound ChEMBLID. The retrieved image can be easily re-sized using the 'dimensions' attribute of the endpoint. See the example URLs below.
• Inclusion of a 'synonyms' property on ChEMBL compound resources. This property will be set for compounds for which there are synonyms available.

Sample urls:

• Retrieve a compound image - https://www.ebi.ac.uk/chemblws/compounds/CHEMBL192/image

• Retrieve a compound image sized to specific dimensions - https://www.ebi.ac.uk/chemblws/compounds/CHEMBL192/image?dimensions=220

The new client can be downloaded from: https://www.ebi.ac.uk/chembl/extra/chemblrestws/chemblRestClient-1.0.5.jar

As always, you're feedback and suggestions for improving the API are most welcome. Please e-mail: chembl-help@ebi.ac.uk.

ATC Code: A03A (incomplete)
Wikipedia: Linaclotide

On Agust 30, the FDA approved Linaclotide (tradename: Linzess; Research Code: MD-1100, ASP-0456), a novel, first-in-class Guanylate Cyclase-C (GC-C) agonist indicated for the treatment in adults of irritable bowel syndrome with constipation (IBS-C), and chronic idiophatic constipation (CIC). CIC is a diagnosis given to people who experience persistent constipation and do not respond to standard treatment. IBS-C is a subtype characterized by chronic abnominal pain, discomfort, bloating and alteration of bowel habits. Linaclotide exherts its therapeutic action by binding to GC-C, resulting in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Increase in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. Linaclotide has been shown, in animal models, to not only accelerate gastrointestinal (GI) transit, but also to reduce intestinal pain, which is thought to be mediated by increased extracellular cGMP.

Other treatments for IBS have been already in the market and these include treatments with antimuscarinic drugs, such as Dicyclomine (approved in 1950; tradename: Bentyl; ChEMBL: CHEMBL1123), Methantheline (approved in 1951, tradename: Banthine; ChEMBL: CHEMBL1201264), a serotonin agonist, such as Tegaserod (approved in 2002; tradename: Zelnorm; ChEMBL: CHEMBL1201332) and a serotonin antagonist, such as Alosetron (approved in 2000; tradename: Lotronex; Chembl: CHEMBL1110) and Lubiprostone (approved in 2006; tradename: Amitiza; ChEMBL: CHEMBL1201134), a chloride channel activator. While these drugs act by either inhibiting the muscarinic action of acethylcholine, or through the activation of the serotonin receptors of the nervous system in the GI tract, or by activating the chloride channels on the GI epithelial cells, Linaclotide represents the first GC-C agonist to ever reach the market.

GC-C (ChEMBL: CHEMBL1795197; Uniprot: P25092) is a 1073 amino-acid long enzyme, which has an extracellular ligand binding domain (PFAM: ANF_receptor), a domain similar to that of protein tyrosine kinases (PFAM: Pkinase_Tyr) and a adenylate and guanylate cyclase catalytic domain (PFAM: Guanylate_cyc).

>GUC2C_HUMAN Heat-stable enterotoxin receptor
MKTLLLDLALWSLLFQPGWLSFSSQVSQNCHNGSYEISVLMMGNSAFAEPLKNLEDAVNE
GLEIVRGRLQNAGLNVTVNATFMYSDGLIHNSGDCRSSTCEGLDLLRKISNAQRMGCVLI
GPSCTYSTFQMYLDTELSYPMISAGSFGLSCDYKETLTRLMSPARKLMYFLVNFWKTNDL
PFKTYSWSTSYVYKNGTETEDCFWYLNALEASVSYFSHELGFKVVLRQDKEFQDILMDHN
RKSNVIIMCGGPEFLYKLKGDRAVAEDIVIILVDLFNDQYFEDNVTAPDYMKNVLVLTLS
PGNSLLNSSFSRNLSPTKRDFALAYLNGILLFGHMLKIFLENGENITTPKFAHAFRNLTF
EGYDGPVTLDDWGDVDSTMVLLYTSVDTKKYKVLLTYDTHVNKTYPVDMSPTFTWKNSKL
PNDITGRGPQILMIAVFTLTGAVVLLLLVALLMLRKYRKDYELRQKKWSHIPPENIFPLE
TNETNHVSLKIDDDKRRDTIQRLRQCKYDKKRVILKDLKHNDGNFTEKQKIELNKLLQID
YYNLTKFYGTVKLDTMIFGVIEYCERGSLREVLNDTISYPDGTFMDWEFKISVLYDIAKG
MSYLHSSKTEVHGRLKSTNCVVDSRMVVKITDFGCNSILPPKKDLWTAPEHLRQANISQK
GDVYSYGIIAQEIILRKETFYTLSCRDRNEKIFRVENSNGMKPFRPDLFLETAEEKELEV
YLLVKNCWEEDPEKRPDFKKIETTLAKIFGLFHDQKNESYMDTLIRRLQLYSRNLEHLVE
ERTQLYKAERDRADRLNFMLLPRLVVKSLKEKGFVEPELYEEVTIYFSDIVGFTTICKYS
TPMEVVDMLNDIYKSFDHIVDHHDVYKVETIGDAYMVASGLPKRNGNRHAIDIAKMALEI
LSFMGTFELEHLPGLPIWIRIGVHSGPCAAGVVGIKMPRYCLFGDTVNTASRMESTGLPL
RIHVSGSTIAILKRTECQFLYEVRGETYLKGRGNETTYWLTGMKDQKFNLPTPPTVENQQ
RLQAEFSDMIANSLQKRQAAGIRSQKPRRVASYKKGTLEYLQLNTTDKESTYF

Linaclotide is an oral peptide drug, comprised of 14 amino acids and with disulfide bonds between cysteines (1-6), (2-10) and (3-15). Linaclotide has a molecular weight of 1526.8 Da. (Name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L­-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5­-13)-tris (disulfide); CanonicalSmiles: C[C@@H](O)[C@@H]1NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@@H](N)CSSC[C@H](NC(=O)[C@H](CSSC[C@H](NC(=O)CNC1=O)C(=O)N[C@@H](Cc4ccc(O)cc4)C(=O)O)NC(=O)[C@H](Cc5ccc(O)cc5)NC(=O)[C@H](CCC(=O)O)NC3=O)C(=O)N[C@@H](CC(=O)N)C(=O)N6CCC[C@H]6C(=O)N[C@@H](C)C(=O)N2; InChI: InChI=1S/C59H79N15O21S6/c1-26-47(82)69-41-25-101-99-22-38-52(87)65-33(13-14-45(80)81)49(84)66-34(16-28-5-9-30(76)10-6-28)50(85)71-40(54(89)72-39(23-97-96-20-32(60)48(83)70-38)53(88)67-35(18-43(61)78)58(93)74-15-3-4-42(74)56(91)63-26)24-100-98-21-37(64-44(79)19-62-57(92)46(27(2)75)73-55(41)90)51(86)68-36(59(94)95)17-29-7-11-31(77)12-8-29/h5-12,26-27,32-42,46,75-77H,3-4,13-25,60H2,1-2H3,(H2,61,78)(H,62,92)(H,63,91)(H,64,79)(H,65,87)(H,66,84)(H,67,88)(H,68,86)(H,69,82)(H,70,83)(H,71,85)(H,72,89)(H,73,90)(H,80,81)(H,94,95)/t26-,27+,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1)

The recommended dosage of Linaclotide is 290 mcg orally once daily for the case of IBS-C, and 145 mcg orally once daily for the treatment of CIC, on empty stomach at least 30 minutes prior to first meal of the day.

Linaclotide is minimally absorbed with low systemic availability following oral administration. Concentrations of Linaclotide and its active metabolite in plasma are below quantitation after oral doses of 145 mcg and 290 mcg were administrated. Therefore Linaclotide is expected to be minimally distributed to tissues. Linaclotide is metabolised within the GI tract to its active metabolite by loss of the terminal tyrosine moiety. Both Linaclotide and the metabolite are proteolitically degraded within the intestinal lumen to smaller peptides and naturally occuring amino acids. Following the daily administration of 290 mcg of Linaclotide for seven days, about 5% and 3% were recovered in the feces of fasted and fed subjects, respectively, and virtually all as the active metabolite.

The license holder is Ironwood Pharmaceuticals, Inc. and the full prescribing information of Linaclotide can be found here.