MRC 22 vs. NCATS 58 repurposing lists: similar but different

Update, December, we have a paper out on the results.

The collaboration between the MRC and AstraZeneca to give UK academic researchers access to development compounds has been acknowledged as a precedent for the compilation of the analogous NCATS 58-set from multiple companies.  A snapshot of the MRC list of 22 is shown below.  

There is plenty of background information about both sets and repurposing exercises in general available on  the web.  In addition,  the associated issue of public code names with  very-difficult-to-dig-out (VDTODO) or completely blinded structures has also generated additional blog posts (e.g. at CollabChem and Chembl-og) 

I have performed the same exercise for these as for the NCATS 56 small molecules. This is a) map the code names to a structure,  b) assign a PubChem CID  and c)  search SureChemOpen for matches to early patent filings. The summary list is pasted below, a more extended table has been deposited at Figshare and a set of links for the 12 CIDs is available as a public MyNCBI collection ( http://www.ncbi.nlm.nih.gov/sites/myncbi/collections/public/1HKfLlxQ0OICuWKEPOFU48tky/)

AZD code	MoA	NCATS		CID	SureChemOpen patent match
AZD0530	SRC Tyrosine Kinase Inhibitor	Yes	http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=10302451	10302451	484 document hits
AZD1236	Matrix Metallopeptidase (MMP) 9|12 Inhibitor	Yes
AZD1656	Glucokinase Activator	Yes	http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=16039797	16039797	https://open.surechem.com/en/document/WO-2007007041-A1/
AZD2624	Neurokinin Receptor NK3 Antagonist		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=23649160	23649160	https://open.surechem.com/en/document/WO-2007069977-A1/
AZD3355	GABABR1 Receptor Agonist		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9833984	9833984	https://open.surechem.com/en/document/WO-2001042252-A1/
AZD4017	11-beta Hydroxysteroid Dehydrogenase Type1Inhibitor
ZD4054	Endothelin A Receptor Antagonist		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9910224	9910224	https://open.surechem.com/en/document/WO-1996040681-A1/
AZD5904	Myeloperoxidase inhibitor		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=10264211	10264211	https://open.surechem.com/en/document/WO-2009025618-A1/
AZD7325	GABAA Ion Channel Stimulator	Yes	http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=23581869	23581869	https://open.surechem.com/en/document/US-20070142382-A1/
AZD8529	Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator
AZD1080	GSK3b Inhibitor
AZD1386	TRPV1 Ion channel Inhibitor
AZD1704	Cannabinoid CB1 receptor Agonist
AZD4619	PPARA Agonist		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=10217984	10217984	https://open.surechem.com/en/document/WO-2003051826-A1/
AZD4769	EGFR Tyrosine Kinase Inhibitor
AZD6088	Muscarinic M1 Receptor Agonist		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=25195463	25195463	https://open.surechem.com/en/document/WO-2009034380-A1/
AZD6605	Matrix Metallopeptidase (MMP) 13 Inhibitor
AZD6703	MAPK14 (p38) tyrosine kinase inhibitor		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11373432	11373432	https://open.surechem.com/en/document/WO-2005042502-A1/
AZD7268	δ-Opioid receptor agonist	Yes	http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=24772484	24772484	https://open.surechem.com/en/document/WO-2008048171-A1/
AZD7687	DGAT Inhibitor
AZD8055	mTOR Serine/Threonine Kinase (mTORC1/2) Inhibitor		http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=25262965	25262965	https://open.surechem.com/en/document/WO-2009153597-A2/

I managed to dig out CIDs mapped to 12 of the 21 codes, but there are 5 compounds-in-common between the MRC and NCATS sets.  Note also we have a patent-mapping full-house for the 12.  These posts are about picking out the quirky details so lets see what we have...

AZD6703 will be a bit of a system test because the publication is recent and neither yet MeSH processed nor picked up by ChEMBL.  It was also a dozy in the Goldilocks school of abstract drafting for lead compounds, as you can see below, where we see no less than the IUPAC, code name, target and indication all in the title (if the abstract had had some inhibition data and included the term "arthritis" this would have been an almost perfect pay-wall bypass!)

IUPACs in titles (where there are no direct MeSH > PubChem links) can be easily processed by chemicalize.org (the result is in the picture insert).  This gives an exact match to CID 11373432  and a patent whack back to WO-2005042502-A1.  However, what is odd is the opening out the MMDB > CID links for the PDB structures gives the set of four below but does not include 11373432.

What I think has happened is the not uncommon story of the ligand going into a crystal structure (i.e. dropped into the tube) not being exactly the same as the structure the software has pulled back out of the electron density data (see below)

 In this case it was CID 56962314 on the left "out" vs presumably CID 11373432 on the right "in".   Note that Thomson Pharma and SureChem independantly corroborate the rendering of the latter wheras the former is an  MMDB orphan. I'll try to get back to reporting what MeSH eventually does with the linking.

I'll finish off with the strange and VDTODO case of disclosing a code name > struc for AZD5904  as an HPLC internal standard.  The only hit you can find is in Google Scholar (below)  not in PubMed via the abstract (PMID 22592983)

The text is slightly cryptic in that the candidate IUPAC (3-[(2R)-tetrahydrofuran-2-ylmethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one) converted by chemicalize.org,  is not explicitly juxtaposed to AZD5904.  However, it is the only one in the paper and it whacks WO-2009025618-A1  "MIPO inhibitors for the treatment of huntington's disease and multiple system atrophy"  which makes it a good bet.