Here at ChEMBL, we are often contacted by users who are interested in purchasing some of the compounds that we store in our databases. However, our compounds are curated directly from the literature and we do not have access to physical samples. To enable our users to find supplier information for the compounds, we have now added direct links from ChEMBL to ChemSpider. ChemSpider is a resource containing millions of chemical structures, with associated property information. This property information also includes supplier information, where available. You can connect to ChemSpidervia our Compound Report Card, under "Database Links" and by clicking on the Standard InchiKey hyperlink you will be taken directly to the same compound in ChemSpider. You can also connect directly to ChEMBLdb via ChemSpider using the hyperlink found under their "Biological Data" tab.
There are 10 distinct drug structures here (some are parent and salt pairs), six are synthetic small molecules, largely from established target classes, and four are biological drugs. Latrepirdine a.k.a. Dimebon is a molecule showing broad pharmacology, and a rollercoaster ride through licensing and development.
On September 14th 2010, the FDA approved Pegloticase under the trade name Krystexxa. Pegloticase is a recombinant enzyme for the treatment of gout and can replace xanthine oxidase (XO) inhibitors for patients who do not respond to or cannot tolerate treatment with xanthine oxidase inhibitors.
Gout is a painful affliction caused by microscopic needle-shaped crystals of sodium urate which precipitate in joints and tendons and stimulate a local inflammatory response. These attacks of inflammatory arthritis not only cause pain and stiffness of the joint, but, if left untreated for years, also damage the cartilage and surrounding tissue. Hard, non-painful deposits of crystalline uric acid known as tophi occur in the joints and sometimes the kidney.
Gout is generally associated with obesity, hypertension, insulin resistance and hyperlipidaemia. In more than half of the cases of diagnosed gout, patients have elevated blood levels of uric acid.
Conventionally, acute gout attacks are ameliorated by administration of non-steroidal anti-inflammatory drugs (NSAIDs) and the levels of uric acid are kept low by restricting diet, and also administration of inhibitors of xanthine oxidase (UniProt: P47989, ChEMBL: 149) such as allopurinol and febuxostat. Some patients however cannot tolerate conventional xanthine oxidase inhibitors because of severe allergic reactions. It is this group of patients that pegloticase has been approved for.
Pegloticase is a recombinant uricase, an enzyme that lowers the levels of puric acid by catalyzing the oxidation of puric acid to allantoin (see image), which in turn is readily eliminated via the kidneys. The uricase enzyme exists in all mammals but is not expressed in humans (Entrez Id of the pseudo-gene: 391051) and many primates. Therefore, pegloticase reduces uric acid levels through a catabolic function that has been relatively recently 'lost' in human evolution.
Pegloticase is a modified version of the mammalian uricase and is expressed in E.coli. Each uricase subunit is conjugated to monomethoxy-polyethylene-glycol (mPEG) and the enzyme occurs as a tetramer weighing ~540 kDa.
Eight milligram of Pegloticase are administered every two weeks as a parenteral infusion. In a single-dose, dose-ranging trial, Pegloticase reduced uric acid levels in a dose dependent manner and for doses of 8mg and 12mg, uric acid levels were kept below 6mg/dL for more than 300 hours (n=4).
Krystexxa comes with a boxed warning regarding anaphylaxis and infusion reactions as in clinical trials it caused anaphylaxis in 6.5% of patients treated with Krystexxa every 2 weeks and infusion reactions in 26% of these patients.
The sequence of Peglocitase is very similar to that of pig uricase (UniProt:P16164)
We are setting off soon to the Science Is Vital meeting in London, although being scientists, I'm surprised we didn't call the rally "Science Is Probably Vital".
It will be a little slow at ChEMBL Manor this week, since we are all on a retreat - setting strategy, trying to solve those long-term issues that you never get round to when based in the office, arguing over the smallest details, etc.. This year we have decided to go to Stonebarrow Manor (and very nice it is to!) in Charmouth in Dorset, one of the villages on Britain's Fossil Coast.
Following some successful initial testing and feedback, we have opened up the Structure-based scoring component for full Open Access - please be aware that this is still be considered to be in a test phase, since the coding pixies are still tinkering away in the background. This used to be known as Strudle, which is a name we will not use externally for structure-based assessment methods - The overall name for the druggability services from the ChEMBL group at the EMBL-EBI will be known as DrugEBIlity - cool name eh? It's got EBI in there, obeys a reasonable linguistic construction (it may even be a heterograph, but I'm not sure), is an atrocious pun, and states our view that drugability has one G. Remember that there is a capital I next the the lowercase l.....
The current portal allows you to search with a sequence, with a PDB code, or to upload a structure of your own. We are still establishing a reasonable capacity and farm priorities for uploaded structures, so please be considerate of other that may wish to use the service. We will keep an eye on the error logs and improve error reporting. If you have any questions, please use the normal Chembl support email address.
If you are interested in using the DrugEBIlity web service as part of your research, you are strongly encouraged to look out on the blog for announcements on a couple of webinars we will be running, which will detail what is actually going on, some limitations with the current implementation, and also some of our experience (e.g. do not use it on homology models and expect to get something useful, unless you have been really careful in your modelling). Remember the scoring is based on the conformational state of the protein structure that is analysed, so try and look at other known protein structures to see if there is potentially an induced, or cryptic 'drugable' site. Finally, bear in mind that it is a statistical method, with some error, it is not meant to be definitive, but acts as a guide.
The intent is to provide download of both the database and also the software, but quite a lot of localization will be required, and providing this capability will depend on the level of demand from the user community.
Here at ChEMBL, we are often contacted by users who are interested in purchasing some of the compounds that we store in our databases. However, our compounds are curated directly from the literature and we do not have access to physical samples. To enable our users to find supplier information for the compounds, we have now added direct links from ChEMBL to ChemSpider. ChemSpider is a resource containing millions of chemical structures, with associated property information. This property information also includes supplier information, where available. You can connect to ChemSpider via our Compound Report Card, under "Database Links" and by clicking on the Standard InchiKey hyperlink you will be taken directly to the same compound in ChemSpider. 
You can also connect directly to ChEMBLdb via ChemSpider using the hyperlink found under their "Biological Data" tab. 
There is another clutch of protein kinase inhibitors (nine) in the latest list of recommended INNS, these are:
Following some successful initial testing and feedback, we have opened up the Structure-based scoring component for full Open Access - please be aware that this is still be considered to be in a test phase, since the coding pixies are still tinkering away in the background. This used to be known as Strudle, which is a name we will not use externally for structure-based assessment methods - The overall name for the druggability services from the ChEMBL group at the EMBL-EBI will be known as DrugEBIlity - cool name eh? It's got EBI in there, obeys a reasonable linguistic construction (it may even be a heterograph, but I'm not sure), is an atrocious pun, and states our view that drugability has one G. Remember that there is a capital I next the the lowercase l.....
