ChEMBL

1. Enter the term 'PDE5' in the search text box 
2. Sketch in the structure of Sildenafil (or use the name look-up function)
3. Change the search type to similarity (>85%) 
4. Click the 'Claims' checkbox in the document filter section and 
5. Hit 'Search' button

After clicking 'Search', you will be presented with a page which contains all compounds that match your search criteria:






 

The second deals with using text mining approaches to find papers that look like they could be abstracted into ChEMBL - that is they contain keywords enriched in medicinal chemistry and compound structure concepts. The abstract for this paper is:

%T UniChem: extension of InChI-based compound mapping to salt, connectivity and stereochemistry layers
%A J Chambers
%A M Davies
%A A Gaulton
%A G Papadatos
%A A Hersey
%A JP Overington
%J Journal of Cheminformatics 
%D 2014
%V 6:43  
%O doi:10.1186/s13321-014-0043-5
%O http://www.jcheminf.com/content/6/1/43

%T A document classifier for medicinal chemistry publications trained on the ChEMBL corpus
%A G Papadatos
%A GJP van Westen
%A S Croset
%A R Santos
%A S Trubian
%A JP Overington
%J Journal of Cheminformatics 
%D 2014
%V 6:40  
%O doi:10.1186/s13321-014-0040-8
%O http://www.jcheminf.com/content/6/1/40

The identity of compounds in the literature is often uncertain - with high profile cases of incorrect compounds being used in experiments - with subsequent difficulties in reconciling conflicting experiments or repeating results.

One example is the kinase inhibitor Bosutinib (SKI-606) - where several compound vendors shipped a similar isomer of the actual drug. It will be unclear which data comes from the bona fide Bosutinib and the compound sold as Bosutinib by multiple vendors. More details on this case are in this post by Derek Lowe, and there is a definitive structural biology paper here. So this probably clouds a lot of the reported Bosutinib bioactivity data that's out there. Here the difference is in the differential substitution pattern on an aromatic ring (2,4-dichloro-5-methoxy vs 3,5-dichloro-4-methoxy), the mass is the same for these isomers.

A second example is this case (a clinical stage compound called TIC10) where there was a mix-up in the structure assigned to a compound in a patent, and since the substance had novel and potentially useful bioactivity and the annotated structure in wrong, led to all sorts of complicated IP issues and shenanigans. Since this compound was also in a widely distributed and profiled NCI set, then the literature ends up with difficult to deconvolute data.

There are probably many of these examples - and here are two more, both connected to clinical development stage protein kinase inhibitors from Exelixis.


The first is XL-765 also known as SAR-245409 and by the INN Voxtalisib - it is a PI3K inhibitor. Compound vendors have been selling 'XL-765' for some time, but the structure sold is (typically) not the correct XL-765 structure.

XL-765 is known to be this structure - multiple independent authoritative source point to this identity. It's a quite simple, small molecule.  The InChI key is RGHYDLZMTYDBDT-UHFFFAOYSA-N.
Several vendors have been selling a different structure as 'XL-765/SAR-245409'; as you will immediately note, it is a very different structure - not a positional or stereo-isomer, it will have very different mass, etc.



Some purchasers of this compound report peer-reviewed in vivo data. To be clear, this isn't just one company, it is all/most vendors of XL-765.


So there are a number of things that could have happened here:

i) The correct structure was supplied, but the structure on the label/on the website didn't match the real physical structure - i.e. a mislabelling.
ii) The incorrect structure was supplied, and the structure on the label/website was what was in the bottle. In our studies (at FIMM) the vendor supplied XL-765 has not behaved as a PI3K inhibitor, so the latter is more likely.

However, the incorrect XL-765 structure has propagated into public chemistry databases, and literature data for XL-765 is probably now largely suspect (with the exception of that from Exelixis themselves (and their collaborators)).

Here's the second new example - XL-147 (aka SAR-245408 and Pilaralisib) - again a PI3K inhibitor. The correct structure is QINPEPAQOBZPOF-UHFFFAOYSA-N.

Many vendors were selling XL-147 as the following compound, here there is a lot more similarity between the actual and sold compound, but it's still different, and any biology on this, although it may well be active in it's own right, is not the same as XL-147.



tl;dr Be careful if you are interested in purchasing or analysing activities and properties of Bosutinib, Pilaralisib &Voxtalisib. Be careful in loading names from Vendor catalogs, and try to use more definitive authorities for compound synonyms. Be careful with relying on things from any public databases.


Krister and I would like to thank Willie Yuan at Chemietek for helping to clarifying aspects of the confusing history for this compound.

jpo and Krister

We will use ChEMBL-og as the primary route of communicating with users, so if you want to be kept up to date, bookmark the site. We will also make ad hoc tweets about SureChEMBL on @johnpoverington, @georgeisyourman, @surechembl and @chembl.

Users familiar with the previous SureChem UI will find a lot in common with the new SureChEMBL UI. A summary of the changes and new features we have added to the SureChEMBL UI are provided below:

In line with ChEMBL IDs, all compounds in SureChEMBL have been given SCHEMBL identifiers. For example, SCHEMBL1353 corresponds to 2-(acetyloxy)benzoic acid, aka aspirin. The identifier can be used to access the SureChEMBL compound page and will be included in all SureChEMBL downloads.

The SureChEMBL pipeline has been running daily throughout the summer and has now processed and extracted an additional ~400,000 novel compounds from patents since SureChem’s pipeline freeze. At the time of writing (16:22 22/08/14), the SureChEMBL counts are:

The rate of novel compounds and annotated patents is truly staggering: There are approximately 80,000 compounds extracted from 50,000 patents that are added to the system every month. Moreover, the latency for a new patent document from its application date to becoming searchable in the system is only between 2 and 7 days, in most cases.

The complete SureChEMBL structure repository has been added to UniChem (src_id=15)  and consists of 15.2M unique structures mapped to their SCHEMBL IDs. SureChEMBL updates will be added to UniChem on a weekly basis, so that UniChem will be up to date with novel patent chemistry.

Besides availability in UniChem, the complete SureChEMBL structure repository is provided as SD and tsv file in our ftp site:

ftp://ftp.ebi.ac.uk/pub/databases/chembl/SureChEMBL/data/

It has to be emphasised here that this is the raw compound feed as extracted automatically from text and images and is provided without any further filtering or manual curation. This feed contains fragments, radicals, atoms with wrong valencies, polymers and other oddities but if you are the sort of person who wants to use this raw data, you will know what and how to filter things you don't like out.

The chemical registry rules between SureChEMBL and ChEMBL have not been fully aligned yet - they use fundamentally different toolkits - so there are sometimes multiple SCHEMBL ids for the same InChI - if you know this is an issue, you will know how to fix it for your local purposes if you download the data.

Initially, the SureChEMBL files on the ftp site will be updated on a quarterly basis.

Going forward we have many plans related to SureChEMBL, some of which are linked to our involvement in the Open PHACTS project. Our current plans include:

You will hear more about these plans over the coming year, but our top priority now is to deliver the new SureChEMBL user interface.

If you have any questions about the new SureChEMBL system and data please get in touch