ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Monday, 31 August 2009

Kinase SARfari - looking for testers

We are testing a number of interfaces to our data at the moment, and have just flipped Kinase SARfari to a public facing server. We are looking for some people willing to test the interface on a number of differing platforms, so if you are interested, please mail us.

An install package is also available, for those wishing to try things on their own machines (however, you'll need some experience in web server config, Catalyst (the MVC, not the modelling package), an Oracle database, and a chemical data cartridge...)

Tuesday, 25 August 2009

Meeting: Translating Protein Structures into Drugs, September 10th, London

There is an excellent meeting on protein structures and drug design at King's College London on September 10th 2009 (i.e. very soon now). In order of importance 1) There are some very good speakers 2) it is one day long, and 3) It is free. Here is a link to the meeting website.

Monday, 24 August 2009

New Drug Approvals - Pt. XVI - Vigabatrin (Sabril)

The next approval for this year, on August 21st, was Vigabatrin (trade name Sabril). Vigabatrin (previously known by the research code MDL-71,754) is an antiepileptic drug indicated as a monotherapy for pedriatic patients 1 month to 2 years of age with infantile spasms (IS) and as an adjunctive therapy for adult patients with refractory complex partial seizures (CPS) who have inadequately responded to several alternative treatments. Vigabatrin has previously been approved in the UK, Mexican, Canadian and Danish markets. Vigabatrin is the first therapy approved for the treatment of IS and a new option as add-on therapy for the adults with CPS. Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA; blockade of GABA-T leads to increased levels of GABA in the central nervous system. This enzyme can also be irreversible inhibited by Gabaculine, a naturally occurring bacterial neurotoxin that acts its activity by covalently binding to activated Vitamin B6 (pyridoxal phosphate), the essential cofactor for GABA-T activity. However, as a result of only binding to the cofactor, the inhibitory action of Gabaculine can be overcome by increasing vitamin B6 intake. Acting in a similar but extended manner, Vigabatrin covalently binds to both GABA-T as well as vitamin B6.

Vigabatrin is a 'small' small-molecule drug (Molecular Weight of only 129.16 g.mol-1), is freely soluble in water, and is closely similar to the natural GABA-T substrate, GABA. Vigabatrin is essentially completely orally absorbed, is widely distributed throughout the body, with a volume of distribution of 1.1 L/Kg, and shows negligible plasma protein binding. Vigabatrin is not significantly metabolized (80% of a dose is recovered as parent drug), although it does induce (upregulate expression) of CYP2C9, and it is eliminated primarily through renal excretion. It has a half-life of 7.5 hours.

Vigabatrin is available in the form of tablets for CPS and as an oral solution for IS. Recommended dosage and full prescribing information can be found here for Vigabatrin tablets and here for Vigabatrin oral solution. Daily dosing is 3g (as 1.5g twice a day), with the low molecular weight, this equates to a relatively very large molar dosage (ca. 23mmol).

Vigabatrin has a boxed warning.

The structure is (±)-4-amino-5-hexenoic acid. It is a GABA analogue and is dosed as a racemic compound, with the S-enantiomer being the pharmcologically active form. The first and most notable chemical feature is the alkene group (the double bonded C-C unit), which forms a irreversible, covalent bond with the enzyme and is therefore essential for its inhibitory activity. Generally, drugs that act via formation of covalent bonds, and especially those that form irreversible covalent bonds, are traditionally viewed unfavourably by medicinal chemists, for two major reasons - firstly, the potential for non-specific interactions and side-effects, and secondly, the potential to the drug-protein complex to be recognised by the immune system and trigger a toxic immune response. However, this trend is surprisingly weak, with several blockbuster drugs having irreversible mechanisms - e.g. Esomeprazole and Clopidogrel. Also important for the activity of Vigabatrin is the primary amine group, which undergoes initial nucleophilic addition to the aldehyde group of Vitamin B6 cofactor, binding covalently to it.

Vigabatrin canonical SMILES: O=C(O)CCC(\C=C)N
Vigabatrin InChI: InChI=1/C6H11NO2/c1-2-5(7)3-4-6(8)9/h2,5H,1,3-4,7H2,(H,8,9)
Vigabatrin ChemDraw: Vigabatrin.cdx

The license holder is Lundbeck Inc. and this is the product website.

Friday, 21 August 2009

Software: #songsincode

I always catch onto these internet phenomenom too late, and here is another example - #songsincode

'location':[-22.970834, -43.191665]

And the next....

var i = {shot:{sheriff:true,deputy:false}}



If you like them, google and thou shalt find more (many, many more). Great kudos via

Wednesday, 19 August 2009

Books: Molecules and Medicine

The ACS exhibition hall has got the usual selection of publishers, and I'm drawn, just like a tramp (as in vagrant) to a pile of discarded cardboard, to the book stands. Todays book is Molecules and Medicine by Corey, Czakó and Kürti. It covers a wide range of range of drugs presented as monographs organised by therapeutic area. Additionally, there is an explanation at the front of some key chemistry concepts that help non-chemists understand the array of representational forms of molecules - most people either 'get' chemistry or they don't, and this introduction may well help. As a minor criticism, I personally find the typesetting and illustrations fussy and inconsistently styled, and it just seems too colorful, but this may well add to the attraction of the book overall for a wider audience.

In summary a good book, buy it as a present, either for yourself, or for elderly relatives, they are always really interested in drugs and disease (but if you do the latter, read it first!)

%T Molecules and Medicine
%A E.J. Corey
%A B. Czakó
%A L. Kürti
%I Wiley Interscience
%D 2007
%O ISBN 978-0-470-22749-7

Tuesday, 18 August 2009

Books: Drug Truths

Large pharma gets a pretty hard time in the press, and it would be fair to say that the public's impression of the industry is negative at the current time, and it is difficult to see how this will change in the short to medium term. This is a shame, and probably largely undeserved - a lot of scientists have a lot of pride in their work and the companies they work for (as of course do salespeople, facilties, manufacturing staff, etc.). However, Health, Politics and Money are a heady and potent mix, as the current discussions over 'Obama's' healthcare reforms show.

Let's be clear, this book is a polemic, and all the better for it!

It addresses and challenges a series of widespread media myths about drug discovery ('most drugs are discovered in academic labs with public money', 'large pharma aren't interested in diseases from the third world', 'they're evil manipulative baby snatchers', ad nauseum). The book does this well (actually, not the last one, I made it up, for impact), with data, factual arguments, and a terse but pacy and readable style. It's written by John LaMattina, ex R&D chief of Pfizer, and there are many examples and stories drawn from Pfizer's history that don't normally make the light of day. The other notable thing in the book is the passion that comes across, the excitement of discovery, the disappointment of setbacks, and the drive of scientists trying to make a difference to healthcare.

As usual, it is also well worth reading alternate opinions in order to form a well balanced view (for example, the similarly excellent book by Marcia Angell, The Truth About the Drug Companies: How They Deceive Us and What to Do About It - I guess that title gives away the authors opinion pretty clearly.

%A J. LaMattina
%T Drug Truths
%I Wiley
%D 2009
%O ISBN 978-0470393185

Monday, 17 August 2009

Updated Drug Icons...

We have made a few changes to the icon set we use for the ChEMBL-og New Drug Monographs, we will also use these (or variants thereof) in some of our other web interfaces. The changes were prompted by some of the things we wished we had included from the start.

An example icon is below.

Which is a synthetic small molecule drug, is rule of five compliant, is topically dosed, is dosed as a single enantiomer, and has a boxed warning.

The various components mean

Drug class
this can either be
Synthetic small molecule
Natural product-derived small molecule
Protein: Monoclonal antibody
Protein: Enzyme
Rule of Five
An image of the number five.
This is either pass or fail - we fail a molecule if it fails to pass all the individual tests (usually people use fail one parameter). We use XlogP (the same as used by PubChem) for the calculations and use 5.0 as a cutoff
New target
An image of a 'bullseye' target.
This is either true or false. The target here refers to the molecular target responsible (or believed to be responsible) for it therapeutic efficacy.
Oral delivery
An image of a capsule.
Parenteral delivery
An image of a syringe.
Topical delivery
An image of an ointment tube.
Some drugs are dosed in multiple forms, so this is why we haven't collapsed these down to a single state). Also this icon actually represents the absorption route (so some drug that are actually deliver orally, may in fact be sublingually absorbed.
Chirally pure
An image of a chiral human hand.
The drug is dosed as a single optically active substance
An image of a par of scissors.
The drug is essentially inactive in the dosed form and requires some chemical change in order to become pharmacologically active against it's efficacy target.
Boxed warning
An image of a black box.
Either true or false.

SME Workshop on European Bioinformatics Resources - Vienna, 3rd and 4th September 2009

There is a workshop in Vienna targeted at SMEs (Small and Medium Enterprises) on the 3rd and 4th September. If you are interested in going, you'd better hurry up since the closing date for registrations is the 21st August.

Sunday, 16 August 2009

New Drug Approvals - Pt. XV - Asenapine (Saphris)

On the 14th August 2009 Asenapine (tradename Saphris) was approved for the acute treatment of schizophrenia in adults and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. This class of psychiatric diseases are complex and carry a significant economic healthcare burden; approximately 24 million people worldwide are believed to suffer from schizophrenia, while ca. 67 million people are thought to suffer from bipolar I disorder. Asenapine (previously known by the research code Org-5222) is the one of a large class of drugs aimed at treating such diseases, and shows the typical broad spectrum of against a variety of receptor targets and a complicated mechanism of action, although such drugs are thought to primarily act through antagonism of D2 and 5HT2A receptors. To give some idea of the promiscuity (or polypharmacology) of Asenapine at various aminergic GPCRs, reported pKis are 5HT1A 8.6, 5HT1B 8.4, 5HT2A 10.2, 5HT2B 9.8, 5HT2C 10.5, 5HT5A 8.8, 5HT6 9.5, 5HT7 9.9, alpha1 8.9, alpha2A 8.9, alpha2B 9.5, alpha2C 8.9, D1 8.9, D2 8.9, D3 9.4, D4 9.0, H1 9.0, and H2 8.2. Asenapine has had quite a complex development and commercial history, as web searches will readily show.

Asenapine is a small molecule drug (Molecular Weight of 285.8 g.mol-1 for Asenapine itself, and 401.84 g.mol-1 for the Asenapine Malate dosed ingredient). Asenapine is reasonably absorbed with an absolute bioavailability of 35% for sublingual dosing - for oral dosing (i.e. the drug makes it into the stomach and bowel absorption is far lower at ca. 2%. (This route of absorption also is really 'topical', even through thr drug is orally dosed, hence the topical icon above - confusing -eh?). Asenapine has high plasma protein binding (~95%), and a volume of distribution of 20-25 It also has a high clearance - 52 Asenapine is primarily metabolized by oxidative metabolism by CYP1A2 and also by direct glucoronidation by UGT1A4, and is cleared by both renal and hepatic routes in approximately similar proportions. It has a an elimination half-life of ca. 24 hours and due to this long half-life, steady-state plasma concentrations are reached after approximately three days. Recommended dosage is one tablet of 5 mg twice daily (equivalent to ca. 24.9 µmol). The full prescribing information can be found here.

Asenapine has a boxed warning.

The Asenapine structure is (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole - and more broadly is member of a set of molecules called dibenzo-oxepino pyrroles. It is fully rule-of-five-compliant. The structure is reasonably unremarkable in terms of its functional group content - the only distinctive feature is the basic amine, but other than being primarily flat, highly rigid and planar, it is difficult to highlight anything more specific.

Asenapine canonical SMILES: CN1CC2C(C1)C3=C(C=CC(=C3)Cl)OC4=CC=CC=C24 Asenapine InChI: InChI=1S/C17H16ClNO/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17) 15(14)10-19/h2-8,14-15H,9-10H2,1H3/t14-,15-/m1/s1 Asenapine InChIKey: VSWBSWWIRNCQIJ-HUUCEWRRSA-N Asenapine CAS registry: 65576-45-6 Asenapine ChemDraw: Asenapine.cdx

The license holder for Asenapine is Schering Plough and the product website is

Tuesday, 11 August 2009

New Drug Approvals - Pt. XIV - Pitavastatin (Livalo)

The latest FDA approval is Pitavastatin (trade name Livalo), approved on August 3rd. Pitavastatin is an HMG-CoA reductase inhibitor, indicated for the primary treatment of hypercholesterolemia (elevated levels of cholesterol in the blood) on patients unable to sufficiently lower their cholesterol levels by diet and exercise. Hypercholesterolemia is a very widespread and leads to serious cardiovascular disease in affluent and increasingly in developing societies.
Pitavastatin (also known by the research code NKS-104) has been available in Japan since 2003 and is now the sixth statin to reach the U.S. market, after Lovastatin (trade name Mecavor), Pravastatin (trade name Pravachol), Fluvastatin (trade name Lescol), Atorvastatin (trade name Lipitor) and Rosuvastatin (trade name Crestor). All of these drugs are derived from the natural product Mevastatin from the fungus Penicillium citrinum. Like the other statins, Pitavastatin lowers the cholesterol levels by competitively inhibiting HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of low-density lipoprotein (LDL) receptors, resulting in a greater low-density lipoprotein cholesterol (LDL-C) clearance and overall reduction of cholesterol from the bloodstream. However, even in this relatively well studied area of biology, there are still many questions to be answered over cholesterol flux and pathogenesis.
Pitavastatin is small-molecule drug (Molecular Weight of 421.5 g.mol-1), and is fully Rule-of-Five compliant. Pitavastatin has a high bioavailability of 51%, and high protein plasma binding (ppb) of 99%), along with volume of distribution of 148 L and a half-life of 11 hours. Metabolism is primarily by glucuronidation (see below) but there is minor oxidative processing by CYP2C9 (and to a lesser by CYP2C8). The major metabolite isolated from human plasma is the lactone is formed via an ester-type pitavastatin glucuronide conjugate catalysed by UGT1A3 and UGT2B7. Excretion is primarily through feces (79% of dose). Typical dosage is of a single 2 mg tablet once a day (equivalent to a daily dose of 4.8 umol).

The structure (3R,5S,6E)-7-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-3,5-dihydroxyhept-6-enoic acid contains a diol group with two defined stereocenters and a free carboxylic acid group (which mimic the mevalonic acid substrate of the enzyme). The acid group will make the drug negatively charged under physiological conditions and dominate its physical chemistry), common features among many synthetic statins. The remainder of the molecule is largely lipophilic and rigid.
Pitavastatin canonical SMILES: O=C(O)CC(O)CC(O)/C=C/c1c(c3ccccc3nc1C2CC2)c4ccc(F)cc4
Pitavastatin InChI: InChI=1/C25H24FNO4/c26-17-9-7-15(8-10-17)24-20-3-1-2-4-22(20)27-2 5(16-5-6-16)21(24)12-11-18(28)13-19(29)14-23(30)31/h1-4,7-12,16,1 8-19,28-29H,5-6,13-14H2,(H,30,31)/b12-11+
Pitavastatin CAS registry: 147511-69-1
Pitavastatin ChemDraw: Pitavastatin.cdx
The license holder is Kowa Pharmaceuticals and the product website is

Saturday, 1 August 2009

New Drug Approvals - Pt. XIII - Saxagliptin (Onglyza)

On the 31st July 2009 Saxagliptin (tradename Onglyza) was approved for the treatment of Type II diabetes - Type 2 Diabetes is also known as adult-onset diabetes, and also non-insulin-dependent diabetes melittus (NIDDM). It is the type of diabetes that is often associated with obesity, and so is an increasingly common disease/condition in our well-fed western and also developing world cultures.

Saxagliptin (previously known by the research code BMS-477118) is the third orally-dosed Dipeptidyl peptidase-IV (or DPP-IV) inhibitor to market, and is in the same mechanistic class as other 'gliptins' - Sitagliptin (tradename Januvia) and Vildagliptin (tradename Galvus/Eucreas) which are both launched and also others such as Alogliptin (aka SYR322) and Linagliptin (aka BI-1356, and expected tradename Ondero), which are in late stage clinical trials. The DPP-IV drug class has had quite a complex development and commercial history, as web searches will readily show.

Saxagliptin is a small molecule drug (Molecular Weight of 315.4 g.mol-1 for Saxagliptin itself, and 334.43 g.mol-1 for the Saxagliptin monohydrate dosed ingredient), and has low aqueous solubility. Saxagliptin is well absorbed and has low plasma protein binding (<30%),>ca. 15.8 µmol) once a day. The full prescribing information can be found here.

The Saxagliptin structure is (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile. It contains a number of interesting chemical groups, and a clear underlying similarity to a dipeptide can be seen in the 2-D structure (the enzyme DPP-IV, a proteinase, cleaves the two N-terminal amino acids of its substrate peptides)). Normally DPP-IV is involved in the inactivation of two endogenous peptides, GLP-1 and GIP, by DPP-4, blocking this degradation potentiates the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans located in the pancreas. The first functional group of note is the nitrile (the triple bonded nitrogen-carbon unit) - this is essential to the inhibitory activity and is found in several of the other 'gliptins. This group forms a reversible, covalent bond with the residue Ser 630 of DPP-IV. Secondly, there is the bulky, hydrophobic adamantane (or (tricyclo[,7]decane) group (this is the 3-D cage like portion of the molecule. Simple substituted adamantanes are sometimes drugs in their own right, for example amantadine, memantine and rimantadine. Within the 'gliptins though, the large bulky adamantyl group blocks an intramolecular cyclisation, which inactivates the inhibitor. These nitrile and adamantyl groups are linked via an amide bond, and an unusual 5,3 fused ring system pyrollidine (which resembles the amino-acid proline, found in the corresponding position of natural substrates).

Saxagliptin canonical SMILES: C1CC2(CC3CC1C(C3)(C2)O)C(C(=O)N4C(CC5C4C5)C#N)N Saxagliptin InChI: InChI=1S/C18H25N3O2/c19-8-13-4-11-5-14(11)21(13)16(22)15(20)17-2-1-12-3-10(6-17)7-18(12,23)9-17/h10-15,23H,1-7,9,20H2/t10?,11?,12?,13-,14-,15+,17?,18?/m0/s1 Saxagliptin InChIKey: SBBHGAZNWZOMBJ-TXTOARCRSA-N Saxagliptin CAS registry: 361442-04-8 Saxagliptin ChemDraw: Saxagliptin.cdx

The license holder for Saxagliptin is Bristol Myers Squibb and the product website is