ChEMBL

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.

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 InChIKey: PJDFLNIOAUIZSL-UHFFFAOYAL
Vigabatrin efficacy target: >sp|P80404|GABT_HUMAN 4-aminobutyrate aminotransferase, mitochondrial SQAAAKVDVEFDYDGPLMKTEVPGPRSQELMKQLNIIQNAEAVHFFCNYEESRGNYLVDVDGNRMLDLYSQISSVPIGYSHPALLKLIQQPQNASMFVNRPALGILPPENFVEKLRQSLLSVAPKGMSQLITMACGSCSNENALKTIFMWYRSKERGQRGFSQEELETCMINQAPGCPDYSILSFMGAFHGRTMGCLATTHSKAIHKIDIPSFDWPIAPFPRLKYPLEEFVKENQQEEARCLEEVEDLIVKYRKKKKTVAGIIVEPIQSEGGDNHASDDFFRKLRDIARKHGCAFLVDEVQTGGGCTGKFWAHEHWGLDDPADVMTFSKKMMTGGFFHKEEFRPNAPYRIFNTWLGDPSKNLLLAEVINIIKREDLLNNAAHAGKALLTGLLDLQARYPQFISRVRGRGTFCSFDTPDDSIRNKLILIARNKGVVLGGCGDKSIRFRPTLVFRDHHAHLFLNIFSDILADFK
Vigabatrin ChemDraw: Vigabatrin.cdx

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

Drug Prescriptions 2008

Here is an interesting dataset, the top 200 branded pharmaceuticals ranked by US prescriptions (usually this sort of data is presented in terms of sales) - the data is originally from www.drugtopics.com. Like many things in life, and science, the ranked frequency distribution cure pretty much approximates a powerlaw curve (a little bit of deviation from a smooth curve within the top ten most prescribed branded drugs though).

Data for the full 200 branded drugs is here

However, things get a little bit more interesting when you include generic drugs into this analysis (for which the data is here, again derived from data at www.drugtopics.com). The most prescribed drug is Hydrocodone/APAP (APAP is also known as paracetamol/acetominophen) with 121,266,000 prescriptions; Lipitor, the most prescribed branded drug, with 49,043,000 prescriptions is actually only the 7th most prescribed drug. Interestingly 40 out of 50 of the most prescribed drugs are generic (80%). This visualisation below I tried to make with Excel, but it made me so mad and frustrated that I had to open a 75dl bottle of Leffe to calm down a little - in Spotfire it was so quick.... For orientation, branded drugs are shown in red, and generic drugs in blue.

And for the top 50, with some visible labels....

Data for the top 200 Branded and 200 Generic (not the same as the top 400 of all drugs!) is here.

Finally, since everyone is interested in sales as well, see below, for a full list of all US Blockbuster Small Molecule Drugs (sales larger than $1bn). Full data is here.

Datasets:

2008 Top 200 Branded Drugs
2008 Top Generic and Branded Drugs
2008 Top 200 Drug Sales

Software: #songsincode

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

{
'name':'Lola',
'occupation':'showgirl',
'fashion':['music','passion'],
'location':[-22.970834, -43.191665]
}

And the next....

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

and....

if(man.silhouetto.size=='small'){scaramouche.do(fandango);if(thunderbolt&&lightning){me.frightened=true}}

If you like them, google and thou shalt find more (many, many more). Great kudos via http://tinyurl.com/lrh2rl

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

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

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

Peptide/protein

Protein: Monoclonal antibody

Protein: Enzyme

Oligonucleotide

Oligosaccharide.

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

Prodrug

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.