The document describes the NCI/CADD Chemical Identifier Resolver, which works as a resolver for different chemical structure identifiers. It allows the conversion of a given structure identifier into another representation or identifier. The resolver indexes over 150 chemical structure databases containing over 120 million structures. It is accessible via a web API that detects the identifier type and performs the requested conversion via calculation or database lookup.

1. Markus Sitzmann 1 , Wolf-Dietrich Ihlenfeldt 2 , and Marc C. Nicklaus 1 [1] Computer-Aided Drug Design Group, Chemical Biology Laboratory, NCI-Frederick, NIH, DHHS [2] Xemistry GmbH, Auf den Stieden 8, D-35094 Lahntal, Germany NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space

3. Chemical Identifier Resolver chemical structure NCI/CADD Identifiers InChI/InChIKey ChemSpider ID PubChem SID/CID chemical names CAS Registry Number NSC number FDA UNII ChemNavigator SID SMILES SD File Chemical Formula ChEBI ID PDB Ligand ID MRV CML SYBYL Line Notation GIF image

4. http://cactus.nci.nih.gov/chemical/structure Works as a resolver for different chemical structure identifiers. Allows one to convert a given structure identifier into another representation or structure identifier. Chemical Identifier Resolver NCI/CADD Web Resources first beta release: July 2009 current release (beta 4): April 2011

6. resolver chemical names IUPAC names (by OPSIN ) CAS numbers SMILES strings IUPAC InChI/InChIKeys NCI/CADD Identifiers CACTVS HASHISY NSC number PubChem SID ChemSpider ID ChemNavigator SID FDA UNII /smiles /names, /iupac_name /cas /inchi, /stdinchi /inchikey, /stdinchikey /ficts, /ficus, /uuuuu /image /file, /sdf /mw, /monoisotopic_mass /formula /twirl, /3d /urls /chemspider_id /pubchem_sid /chemnavigator_sid “ identifier” “ representation” http://cactus.nci.nih.gov/chemcial/structure Chemical Identifier Resolver NCI/CADD Public Web Resources

7. identifier representation http request http response detection of the identifier type identifier is a full structure representation (e.g. SMILES, InChI) calculation of the requested structure representation identifier is a hashed structure representation (e.g. InChIKey), trivial name etc. database lookup MIME type Chemical Identifier Resolver NCI/CADD Web Resources structure e.g. InChI, GIF image e.g. CAS number, chemical name CACTVS NCI/CADD Chemical Structure Database (CSDB)

8. identifier representation http request http response identifier is a full structure representation (e.g. SMILES, InChI) calculation of the requested structure representation identifier is a hashed structure representation (e.g. InChIKey), trivial name etc. database lookup MIME type Chemical Identifier Resolver NCI/CADD Web Resources structure e.g. InChI, GIF image e.g. CAS number, chemical name CACTVS NCI/CADD Chemical Structure Database (CSDB) detection of the identifier type

9. <request string=&quot; L-alanin &quot; representation=&quot; smiles &quot;> <data id=&quot; 1 &quot; resolver=&quot; name_by_chemspider &quot; string_class=&quot; Chemical Name (ChemSpider) &quot;> <item id=&quot; 1 &quot;> C[C@H](N)C(O)=O </item> </data> <data id=&quot; 2 &quot; resolver=&quot; name_by_opsin &quot; string_class=&quot; IUPAC Name (OPSIN) &quot;> <item id=&quot; 1 &quot;> C[C@H](N)C(O)=O </item> </data> <data id=&quot; 3 &quot; resolver=&quot; name_by_cir &quot; string_class=&quot; Chemical Name (CIR) &quot;> <item id=&quot; 1 “> C[C@H](N)C(O)=O </item> </data> </request> http://cactus.nci.nih.gov/chemical/structure/ L-alanin /smiles/xmls ?resolver= name_by_chemspider , name_by_opsin , name_by_cir Chemical Identifier Resolver NCI/CADD Web Resources

13. original structure record Molfile SDF SMILES ChemDraw cdx PDB structure normalization parent structure SDF SMILES database NCI/CADD Identifier hashcode calculation E_HASHISY NCI/CADD Structure Identifiers Unique Representation of Chemical Structures

15. Fragments Isotopes Charges Stereo Tautomers FICTS FICuS uuuuu sensitive / not sensitive <CACTVS hashcode (E_HASHISY)>-<tag>-<version>-<checksum> Na + 4A122D094098B50D -FICTS-01-1D 0E26B623DF7FAD30 -FICuS-01-70 9850FD9F9E2B4E25 -uuuuu-01-27 NCI/CADD Structure Identifiers Unique Representation of Chemical Structures H N N N H 2 O - O

16. H N N N H 2 O - O N a + charged form tautomer isotope salt stereoisomers “ errors” histidine N N H N H 2 O H O H N N O H O N H 2 H N N O H O N H 2 H N N N H 3 + O - O O H N N N H 2 O N a H N N N H O H O N H N 1 5 N H 2 O H O H N N N H 2 O H O

17. A3DAE0788050DDE4-FICTS E5F83F10C5DB080A -FICTS B2FDA68AEDA06DB9-FICTS 9850FD9F9E2B4E25 -FICTS E5F83F10C5DB080A -FICTS E92E4BA2869F3611-FICTS 8A7AD1EB498CC76A-FICTS 6C16DE2351F9FF50-FICTS H N N N H 2 O - O N a + 9850FD9F9E2B4E25 -FICTS charged form tautomer isotope salt stereoisomers FICTS “ errors” histidine H N N N H 2 O H O N N H N H 2 O H O H N N O H O N H 2 H N N O H O N H 2 H N N N H 3 + O - O O H N N N H 2 O N a H N N N H O H O N H N 1 5 N H 2 O H O

18. A3DAE0788050DDE4-FICuS E5F83F10C5DB080A -FICuS B2FDA68AEDA06DB9-FICuS 9850FD9F9E2B4E25 -FICuS E5F83F10C5DB080A -FICuS E92E4BA2869F3611-FICuS 8A7AD1EB498CC76A-FICuS 9850FD9F9E2B4E25 -FICuS H N N N H 2 O - O N a + charged form tautomer isotope salt stereoisomers FICuS “ errors” 9850FD9F9E2B4E25 -FICuS histidine N N H N H 2 O H O H N N O H O N H 2 H N N O H O N H 2 H N N N H 3 + O - O O H N N N H 2 O N a H N N N H O H O N H N 1 5 N H 2 O H O H N N N H 2 O H O

19. 9850FD9F9E2B4E25 -uuuuu 9850FD9F9E2B4E25 -uuuuu 9850FD9F9E2B4E25 -uuuuu 9850FD9F9E2B4E25 -FICuS 9850FD9F9E2B4E25 -uuuuu 9850FD9F9E2B4E25 -uuuuu 9850FD9F9E2B4E25 -uuuuu 9850FD9F9E2B4E25 -uuuuu H N N N H 2 O - O N a + charged form tautomer isotope stereoisomers salt uuuuu “ errors” 9850FD9F9E2B4E25 -uuuuu histidine N N H N H 2 O H O H N N O H O N H 2 H N N O H O N H 2 H N N N H 3 + O - O O H N N N H 2 O N a H N N N H O H O N H N 1 5 N H 2 O H O H N N N H 2 O H O

20. HNDVDQJCIGZPNO -UHFFFAOYSA-N HNDVDQJCIGZPNO -CDYZYAPPSA-N HNDVDQJCIGZPNO -RXMQYKEDSA-N HNDVDQJCIGZPNO -YFKPBYRVSA-N HNDVDQJCIGZPNO - UHFFFAOYSA -N H N N N H 2 O - O N a + charged form tautomer isotope stereoisomers salt Std. InChIKey “ errors” HNDVDQJCIGZPNO - UHFFFAOYSA -N UHPNKBYGGMJTIM -UHFFFAOYSA-M UHPNKBYGGMJTIM -UHFFFAOYSA-M histidine HNDVDQJCIGZPNO - UHFFFAOYSA -N N N H N H 2 O H O H N N O H O N H 2 H N N O H O N H 2 H N N N H 3 + O - O O H N N N H 2 O N a H N N N H O H O N H N 1 5 N H 2 O H O H N N N H 2 O H O

21. original record original record original record original record original record original record original record original record original record original record original record NCI/CADD Chemical Structure Database Structure Normalization 119.8 million original structure records in CSDB

22. FICTS original record original record original record original record FICTS original record original record original record original record original record original record original record FICTS FICTS FICTS FICTS FICTS FICTS 83.1 million FICTS parent structures 119.8 million original structure records in CSDB NCI/CADD Chemical Structure Database Structure Normalization

23. FICTS original record original record original record original record FICTS original record original record original record original record original record original record original record FICTS FICTS FICTS FICTS FICTS FICTS FICuS FICuS FICuS FICuS FICuS FICuS 83.1 million FICTS parent structures 81.6 million FICuS parent structures 119.8 million original structure records in CSDB NCI/CADD Chemical Structure Database Structure Normalization

24. FICTS original record original record original record original record FICTS original record original record original record original record original record original record original record FICTS FICTS FICTS FICTS FICTS FICTS FICuS FICuS FICuS FICuS FICuS FICuS uuuuu uuuuu uuuuu uuuuu 83.1 million FICTS parent structures 81.6 million FICuS parent structures 76.2 million uuuuu parent structures 119.8 million original structure records in CSDB NCI/CADD Chemical Structure Database Structure Normalization

25. FICTS original record original record original record original record FICTS original record original record original record original record original record original record original record FICTS FICTS FICTS FICTS FICTS FICTS FICuS FICuS FICuS FICuS FICuS FICuS uuuuu uuuuu uuuuu uuuuu tautomer- invariant 83.1 million FICTS parent structures 81.6 million FICuS parent structures 76.2 million uuuuu parent structures 119.8 million original structure records in CSDB NCI/CADD Chemical Structure Database Structure Normalization

26. Tautomer Analysis How much “chemical space” is “just generated” by drawing tautomers?

29. FICuS FICuS FICuS FICuS FICuS FICuS 70.6 million FICuS parent structures NCI/CADD Chemical Structure Database Tautomer Analysis starting from the set of FICuS parent structures we systematically generated all tautomers based on the 21 SMIRKS rule set available in CACTVS generated 680 million tautomers for 1.7% of the FICuS parent structures the enumeration was not exhaustive (2009 DB version)

30. NCI/CADD Chemical Structure Database Tautomer Analysis number database releases 0 10 20 30 40 50 60 70 80 90 0.0 0.5 1.0 1.5 2.0 frequency tautomeric overlap within each individual database release (%) average: ~0.3% of original structure records

31. NCI/CADD Chemical Structure Database Tautomer Analysis number database releases 0 10 20 30 40 50 60 70 80 90 0.0 0.5 1.0 1.5 2.0 frequency tautomeric overlap within each individual database release (%) average: ~0.3% of original structure records Asinex ChemBridge ComGenex ChemNavigator Columbia University Molecular Screening Center EPA DSSTox Specs Ambinter BIND BindingDB ChemNavigator KEGG NCI Open Database NIST WebBook NLM ChemIDplus NMRShiftDB Thomson Pharma Wombat NCI/DTP PASS Training Set SGC-Ox ChemDB ZINC ChEBI ChemSpider

32. NCI/CADD Chemical Structure Database Tautomer Analysis 0 5 10 15 20 25 30 0.5 2.5 4.5 6.5 8.5 10.5 12.5 14.5 16.5 18.5 20.5 22.5 24.5 frequency number database releases percentage of FICuS parent structure in each database release occurring somewhere in CSDB with a conflict occurrence of “tautomerism-critical” molecules within each individual database release (%) average: ~9.5% of FICuS parent structures

34. HPMBP (1-Phenyl-3-methyl-4-benzoyl-pyrazolone-5) CACTVS generates 7 tautomers Example for a Tautomer “Conflict” canonical tautomer by CACTVS 5 tautomers have potential stereo center on atoms or bonds N N O H O H N N O O H N N O O R/S H N N O H O H R/S H N N O O H E/Z N N O O H E/Z N N O O R/S

35. H H 4551-69-1 33064-14-1 127117-31-1 859 references 49 references 3 references HPMBP (1-Phenyl-3-methyl-4-benzoyl-pyrazolone-5) 3 tautomers have CAS Registry Numbers assigned Example for a Tautomer “Conflict” (no stereo) (Z) N N O O H N N O O H N N O O R/S H N N O H O H R/S N N O O H E/Z N N O O H E/Z N N O O R/S

36. N N O H O N N O O N N O O H H N N O O H H N N O H O H H N N O O 6 databases 16 databases (no stereo) 3 databases (R) 2 databases (S) 12 databases 1 database (no stereo) HPMBP (1-Phenyl-3-methyl-4-benzoyl-pyrazolone-5) Example for a Tautomer “Conflict” occurrences in databases indexed in CSDB R/S R/S E/Z E/Z R/S H N N O O

37. 6 databases 16 databases (no stereo) 3 databases (R) 2 databases (S) 12 databases occurrences in databases N N O H O 1 database (no stereo) HPMBP (1-Phenyl-3-methyl-4-benzoyl-pyrazolone-5) Example for a Tautomer “Conflict” ACD 3D Ambinter BindingDB ChemBank ChemDB ChemSpider ChemNavigator MLSMR NIAID Scripps Screening Center Thomson Pharma ZINC ChemDB ACD 3D ACX Ambinter BioByte QSAR ChemBank ChemBridge ChemDB ChemSpider DiscoveryGate EPA GCES MLSMR NCI Open Database NIST MS-Lib NLM ChemIDplus Sigma-Aldrich Thomson Pharma Ambinter ChemDB ChemSpider DiscoveryGate ChemNavigator Thomson Pharma ChemSpider ZINC ChemSpider ECOTOX ZINC N N O O R / S H N N O O N N O O H E / Z H N N O O H E / Z H N N O H O H R / S H N N O O R / S

38. Scaffold Analysis

39. Scaffold Analysis NCI/CADD Chemical Structure Database molecular scaffold tree archetype scaffold simple scaffold Schuffenhauer et al. J. Chem. Inf. Model. 2007 , 47 , 47-58 Bemis et al. J. Med. Chem. 1996, 39 , 2887-2893 Bemis et al. J. Med. Chem. 1996, 39 , 2887-2893 S O O N N O level 2 level 1 example N N H O N N H O N N H

40. NCI/CADD Chemical Structure Database 76.2 million CSDB Scaffold Analysis uuuuu compound set

41. NCI/CADD Chemical Structure Database molecular scaffold tree archetype scaffold simple scaffold 76.2 million 8.1 million scaffolds 6.8 million scaffolds 0.8 million scaffolds CSDB Scaffold Analysis uuuuu compound set level 2 level 1 N N H O O N N H N N H

42. NCI/CADD Chemical Structure Database 76.2 million number of unique scaffolds per hierarchy level CSDB Scaffold Analysis uuuuu compound set 8.1 million scaffolds 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 4 5 6 7 8 9 10 Hierarchy Level Number of Unique Scaffolds (in millions) 0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 Number of unique structures (in million) level 2 level 1 molecular scaffold tree N N H O O N N H

43. Atom Neighborhoods

44. Multilevel Neighborhoods of Atoms (MNA) HC C(C(CC-H)C(CC-C)-H(C)) HO C(C(CC-H)C(CN-H)-H(C)) CHCC C(C(CC-H)C(CN-H)-C(C-O-O)) CHCN C(C(CC-H)N(CC)-H(C)) CCCC C(C(CC-C)N(CC)-H(C)) CCOO N(C(CN-H)C(CN-H)) NCC -H(C(CC-H)) OHC -H(C(CN-H)) OC -H(-O(-H-C)) -C(C(CC-C)-O(-H-C)-O(-C)) -O(-H(-O)-C(C-O-O)) -O(-C(C-O-O)) NCI/CADD Chemical Structure Database Filimonov D., Poroikov V., Borodina Yu., Gloriozova T. J. Chem. Inf. Comput. Sci., 1999 , 39 (4), 666-670. MNA level 1 MNA level 2 N O H O H H

45. Multilevel Neighborhoods of Atoms (MNA) NCI/CADD Chemical Structure Database 76.2 million CSDB uuuuu compound set

46. Multilevel Neighborhoods of Atoms (MNA) NCI/CADD Chemical Structure Database Unique MNAs level 1 level 2 13,426 918,516 76.2 million CSDB uuuuu compound set

47. Multilevel Neighborhoods of Atoms (MNA) NCI/CADD Chemical Structure Database Unique MNAs level 1 level 2 13,426 918,516 2.3 billion relationships 1.3 billion relationships ~ 17 MNAs per uuuuu parent structure ~ 30 MNAs per uuuuu parent structure 76.2 million CSDB uuuuu compound set

48. Multilevel Neighborhoods of Atoms (MNA) NCI/CADD Chemical Structure Database surprising: 424,784 MNAs (level 2) are exclusive to a set of 1,3 million structures in ChemSpider Unique MNAs level 1 level 2 13,426 918,516 2.3 billion relationships 1.3 billion relationships ~ 17 MNAs per uuuuu parent structure ~ 30 MNAs per uuuuu parent structure 76.2 million CSDB uuuuu compound set

49. Chemical Structure Web Services NCI/CADD web service NCI/CADD web service NCI/CADD Chemical Structure Database (CSDB) CACTVS external (web) services http Chemical Identifier Resolver other software packages e.g. OPSIN Chemical Structure Web Services NCI/CADD Web Resources

50. IUPHAR DATABASE http://www.iuphar-db.org http://www.akosgmbh.eu/globalsearch/index.htm CACTVS http://www.xemistry.com gChem Virtual Molecular Model Kit http://chemagic.com/web_molecules/script_page_large.aspx Chemical Identifier Resolver NCI/CADD Web Resources Symyx Draw Resolver http://www.symyx.com/ webel.py - A Cinfony module http://baoilleach.blogspot.com/2009/11/ introducing-webel-cheminformatics.html avogadro.openmolecules.net/

51. Chemical Structure Lookup Service II Work in progress …

52. Chemical Structure Lookup Service II Work in progress …

53. Acknowledgments ChemNavigator Scott Hutton Tad Hurst Thanks to all database providers! http://cactus.nci.nih.gov Our web site: University of Cambridge Daniel Lowe Peter Murray-Rust Noel’ O Boyle (University College Cork, Ireland) Richard Apodaca (Metamolecular) Hans-Juergen Himmler CADD Group, CBL, NCI Igor Filippov ChemSpider Antony Williams Valery Tkachenko

54. http://cactus.nci.nih.gov/chemical/structure Chemical Identifier Resolver NCI/CADD Web Resources http://cactus.nci.nih.gov/blog

55. Acknowledgments - Software Python Web Framework Python SQL library Javascript library Peter Ertl CACTVS ChemWriter