This document discusses tools for extracting chemical structures from biomedical documents and connecting that information to databases. It notes that while millions of structures are in databases, many more remain "entombed" in unextracted documents. New tools like Chemicalize.org, OPSIN, and InChI indexing by Google have helped extract and analyze structures across sources. Extracted structures can be connected to databases like PubChem. The document outlines estimates of remaining unextracted structures and provides examples of using various tools to extract, analyze, connect, and share chemical information from texts and across sources in order to make more knowledge openly accessible.

1. Open, Collaborative, and Transformative:
Exploring and Connecting Bioactive
Chemistry Across Biomedical Documents
and Databases with Public Tools
Christopher Southan
TW2Informatics, Göteborg, Sweden,
BioIT Track 11, Boston, April 2013
[1]

2. Dr Christopher Southan, Ph.D., M.Sc.,B.Sc.
TW2Informatics: http://www.cdsouthan.info/Consult/CDS_cons.htm
Mobile: +46(0)702-530710
Skype: cdsouthan
Email: cdsouthan@hotmail.com
Twitter: http://twitter.com/#!/cdsouthan
Blog: http://cdsouthan.blogspot.com/
LinkedIN: http://www.linkedin.com/in/cdsouthan
Publications: http://www.citeulike.org/user/cdsouthan/order/year,,/publications
Presentations: http://www.slideshare.net/cdsouthan
[2]

3. Abstract
Although there are ~ 50 million chemical structure in public databases, many
millions of bioactive compounds are still entoombed in documents. In addition
linking chemistry between patents, papers, abstracts and databases has been
patchy. However, new tools such as chemicalize.org, OPSIN, OSCA, Venny,
CheS-Mapper and InChIKey indexing by Google, have transformed the
extraction, analysis and connectivity of structures from text. Extractions can also
be triaged against PubChem that now contains 14.5 million patent-extracted
compounds from SureChemOpen, SCRIPDB, Thomson and IBM as well as 1
million from journals via ChEMBL and PubMed. These advances present new
collaborative options such as sharing extracted neglected disease patents with
SAR annotations on figshare.
[3]

4. Getting chemistry out of text and linking to data:
some is done but we have to dig for the rest
[4]

5. Estimates for chemical text tombs
• Journal chemistry public extraction, ~10 to 20 million entombed ?
• Majority of useful patent chemistry already publically extracted, but, ~5
to 10 million still to go?
• PubMed abstracts and MeSH chemistry ~ 0.5 million still entombed ?
• Other unique, useful, text-only (i.e. no database cross-references)
chemistry on the web ~ 0.1 to 0.5 million entombed ?
[5]

6. What’s out there: publically disinterred structures
• InChIKey in Google ~ 50 million
• PubChem = 48 million
• PubChem ROF + 250-800 Mw (lead-like) = 31 million
• ChemSpider = 28 million
• PubChem all docs (papers & patents) = 16 million
• PubChem patents = 15 million
• SureChemOpen = 13 million
• PubChem journal sources (PubMed + ChEMBL) = 1 million
~90% of all structures in databases have their primary origin in text sources
[6]

7. Medicinal chemistry patents (tombs with lids off)
• 18,777,229 patents, 2,208,422 WO’s (i.e. ~ 9 per family)
• WO, C07 or A61= 469,856
• WO , C07D or A61K = 235,854
• WO, C07D = 72,737 (assignee vs. year plots below)
[7]

8. PubMed at 22 mill:
~ 10% with chemistry (guarded tombs)
“Free full text” = 575,513 (24%)
[8]

9. Top-5 Med Chem journals (4% lids off tombs)
“Free full text” = 2671 (4.3%)
[9]

10. Growth:
(escaping the
tombs)
• Patent “big bang”
(SureChem &
SCRIPDB in
2012)
• Literature “slow
burn” (ChEMBL
2009 jump)
• Paradox -
patents:papers
15:1
(both sets of CIDs
cumulative)
[10]

11. Patents in PubChem:
post-bang total vs. unique content
PubChem at 47.3 million CIDs, 32% include patents, 20% patent-only
[11]

12. Citations: connections between tombs
but still need to disinter structures
Papers Abstracts
PubMed
Patents
"relatedness"
heuristics
[12]

13. Databases <> structures < > documents:
links, but few reciprocal
Papers Abstracts
0.8 mill
(ChEMBL)
12K 0.2 mill (mainly MeSH)
Patents
15 mill
[13]

14. Post-document retrieval: basic questions
1. What is the name:IUPAC:image:other ratio in the document?
2. Which tools might be appropriate for first-pass extractions?
3. How many and what proportion of strucs can be extracted?
4. Which SAR /in vivo/clinical data is linked to strucs ?
5. Which document sections include the key strucs ?
6. Which database entries have links (back) to this document?
7. Which strucs have InChIKey matches in Google, & database entries?
8. Which strucs have synthesis data?
9. What other documents specify and/or cite this struc ?
10. Which database records for this struc have links to other documents?
11. What realtionship connections can be made using similarity searches?
12. What intersects and differences are discernible within a document set ?
[14]

15. Triaging document or webpage chemistry
• Identify the structure specification types, e.g.
– Semantic names (all sources)
– Code names (press releases, papers and abstracts)
– IUPAC names (papers, patents and abstracts)
– Images (papers, patents, & Google images)
– SMILES (open lab books)
– InChi strings (open lab books)
– SDF files (open lab books, & github)
Convert these to a structure (e.g. SDF, SMILES, InChI) then:
– Search InChIKey in Google
– Search major databases
– Search SureChemOpen
– Compare extracted sets for intersects and diffs
– Extend exact match connectivity with similarity searching
[15]

16. Triage example:
antimalarial
starting point
The MMV390048 code
name is linked to an
image in press reports
but is PubChem and
PubMed -ve
[16]

17. Images: convert and search
Real chemists sketch them in a jiffy;
the rest of us can use OSRA: Optical Structure Recognition Application
(after editing, CS(=O)(=O)c3ccc(C2=CN=C(N)C(C1=CCC(C(F)(F)F)N=C1)C2)cc3)
[17]

18. Making connections:
image > strucure > database > documents
CID 53311393 > ChEMBL > PubMed
SureChem or chemicalize.org > patent
[18]

19. Patent SAR from WO2011086531:
Collating activities via SureChemOpen
CID 53311393 >
[19]

20. Patent SAR results: top-20 from 39 IC50s
[20]

21. Results > figshare
http://figshare.com/articles/Patent_SAR_for_MMV390048/657979
[21]

22. Structures > MyNCBI
http://www.ncbi.nlm.nih.gov/sites/myncbi/collections/public/1zWhcobieZ
bIouGfUdsdbHek5/.
[22]

23. SAR Table: iOS app
from Molecular
Materials
Informatics
SureChemOpen strucs ->
manual data collation ->
PubChem CIDs -> SDF ->
Dropbox -> SAR Table
-> edit in data, R-group
decompose
-> share
[23]

24. InChIKey in Google: instant orthogonal joining
[24]

25. Chemicalize.org: 413 strucs from WO2011086532
CID 53311393 ->
[25]

26. Using OPSIN and chemcalize.org to fix
recalcitrant IUPACs from WO2011086532
Can quasi-manually extract ~ 10 more “split IUPAC” examples
[26]

27. Clustering document extraction sets: CheS-Mapper
WO2011086531 -> chemicalize.org -> 413 cpds download ->
CheS-Mapper -> cluster 8 -> export 53 cpds
[27]

28. PubChem -> ChEMBL -> PMID -> assay -> strucs
• CHEMBL2041980 (structure)
• PMID 22390538 (paper)
• CHEMBL2045642 (assay for 32 strucs
from paper)
• The 32 CIDs all have patent matches
•
[28]

29. Venny: intersects, diffs, de-dupes and merges
1) WO2011086531
matches in
PubChem
2) CheS-Mapper
cluster 8 from
WO2011086532
3) ChEMBL
assayed cpds from
PMID 22390538
(handles any
regular strings e.g.
db IDs, SMILES,
IChI or InChIKey)
[29]

30. OSDDMalaria: global sharing test-bed
• Different options being explored
• Team or personal URLs >chemicalize.org
• Github for SD files
• PubChem public collections
• Direct feed to ChEMBL malaria
• G+ for real-time exchange and feedback
[30]

31. The open toolbox facilitates extraction and
collation of 10 to 30 million structures
entombed in text
[31]

32. Conclusions
• The ability to extract chemical structures from text and web sources
has been transformed by an expansion of the public toolbox
• The PubChem big-bang increases probability of extraction having
database exact or similarity matches
• Paradoxically, the patent corpus is now completely open while access
to journal text is still restricted
• However, ChEMBL has extracted ~ 0.8 mill. SAR-linked and target
mapped structures from ~ 50K papers
• The submission of ~15 mill. patent structures to PubChem ensures at
least representation from the majority of medicinal chemistry patents
(many of which spawned the subsequent ChEMBL papers)
• Those who want to share their structures globally (e.g. OSDD) have an
expanding set of options for surfacing their results.
[32]