NCICADD Chemical Identifier Resolver Indexing and Analysis of

NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space 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 Gmb. H, Auf den Stieden 8, D-35094 Lahntal, Germany NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Small Molecule Databases • since the early 2000 s: number of databases “publishing” small molecules grew enormously, e. g. Pub. Chem, Chem. Spider, Ch. EMBL, Drug. Bank – what is the overlap, how many small-molecules are there currently? • ambiguities in the representation of small molecules (e. g. tautomerism, salts, ionic resonance forms) • growing number of chemical structure identifiers (In. Ch. I/In. Ch. IKey, Pub. Chem SID/CID, Chem. Spider ID, Ch. EBI ID, …) NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Chemical Identifier Resolver SMILES SYBYL Line Notation CAS Registry Number chemical names GIF image SD File Chem. Navigator SID CML chemical structure FDA UNII NCI/CADD Identifiers NSC number In. Ch. I/In. Ch. IKey MRV Pub. Chem SID/CID Chem. Spider ID Chemical Formula NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space Ch. EBI ID PDB Ligand ID U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Web Resources Chemical Identifier Resolver Works as a resolver for different chemical structure identifiers. Allows one to convert a given structure identifier into another representation or structure identifier. first beta release: July 2009 current release (beta 4): April 2011 http: //cactus. nci. nih. gov/chemical/structure NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Web Resources Chemical Identifier Resolver • it is usable by a simple URL API: http: //cactus. nci. nih. gov/chemical/structure/”identifier”/”representation” XML format: http: //cactus. nci. nih. gov/chemical/structure/”identifier”/”representation”/xml example: http: //cactus. nci. nih. gov/chemical/structure/Tamiflu/cas 204255 -11 -8 MIME type: text/plain • if a request is not resolvable: HTTP 404 status message NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Public Web Resources Chemical Identifier Resolver chemical names IUPAC names (by OPSIN) CAS numbers SMILES strings IUPAC In. Ch. I/In. Ch. IKeys NCI/CADD Identifiers CACTVS HASHISY NSC number Pub. Chem SID Chem. Spider ID Chem. Navigator SID ZINC FDA UNII resolver http: //cactus. nci. nih. gov/chemcial/structure “identifier” NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space /smiles /names, /iupac_name /cas /inchi, /stdinchi /inchikey, /stdinchikey /ficts, /ficus, /uuuuu /image /file, /sdf /mw, /monoisotopic_mass /formula /twirl, /3 d /urls /chemspider_id /pubchem_sid /chemnavigator_sid “representation” U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Web Resources Chemical Identifier Resolver representation identifier MIME type http request detection of the identifier type identifier is a hashed structure representation (e. g. In. Ch. IKey), trivial name etc. calculation of the requested structure representation identifier is a full structure representation (e. g. SMILES, In. Ch. I) http response e. g. In. Ch. I, GIF image structure database lookup NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space CACTVS e. g. CAS number, chemical name NCI/CADD Chemical Structure Database (CSDB) U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Web Resources Chemical Identifier Resolver representation identifier MIME type http request detection of the identifier type identifier is a hashed structure representation (e. g. In. Ch. IKey), trivial name etc. calculation of the requested structure representation identifier is a full structure representation (e. g. SMILES, In. Ch. I) http response e. g. In. Ch. I, GIF image structure CACTVS e. g. CAS number, chemical name database lookup NCI/CADD Chemical Structure Database (CSDB) NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Chemical Identifier Resolving Chemical Names http: //cactus. nci. nih. gov/chemical/structure/L-alanin/smiles/xmls ? resolver=name_by_chemspider, name_by_opsin, name_by_cir <request string="L-alanin" representation="smiles"> <data id="1" resolver="name_by_chemspider" string_class="Chemical Name (Chem. Spider)"> <item id="1">C[C@H](N)C(O)=O</item> </data> <data id="2" resolver="name_by_opsin" string_class="IUPAC Name (OPSIN)"> <item id="1">C[C@H](N)C(O)=O</item> </data> <data id="3" resolver="name_by_cir" string_class="Chemical Name (CIR)"> <item id="1“>C[C@H](N)C(O)=O</item> </data> </request> NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Chemical Identifier Resolver Chemical Structure Database (CSDB) • Chem. Navigator i. Research Library compilation of commercially available screening compounds from ~330 international chemistry suppliers • Pub. Chem database including Open NCI database, EPA DSSTox databases, NIAID HIV databases, NIST Webbook, NLM Chem. IDplus, Chem. Spider … • Commercial Sources / others Asinex, Comgenex, e. Molecules, Ch. EMBL, … NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space Chem. Nav. i. Research Lib. ~56% Pub. Chem ~38% ~6% others currently: ~150 chemical structure databases ~120 million structure records ~81. 6 million unique structures by NCI/CADD FICu. S Identifier ~84 million unique structures by Std. In. Ch. IKey U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Structure Identifiers FICTS, FICu. S, uuuuu NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Unique Representation of Chemical Structures NCI/CADD Structure Identifiers • based on hashcodes calculated by the chemoinformatics toolkit CACTVS O HN OH N NH 2 9850 FD 9 F 9 E 2 B 4 E 25 • CACTVS hashcodes: § represent a chemical structure uniquely as 16 -digit hexadecimal number (64 -bit unsigned) § high sensitivity to structural features of a compound § change if connectivity changes NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Unique Representation of Chemical Structures NCI/CADD Structure Identifiers Molfile SDF SMILES Chem. Draw cdx PDB original structure record structure normalization parent structure hashcode calculation E_HASHISY NCI/CADD Identifier SDF SMILES database NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Unique Representation of Chemical Structures NCI/CADD Structure Identifiers Molfile SDF SMILES Chem. Draw cdx PDB original structure record structure normalization parent structure hashcode calculation E_HASHISY SDF SMILES database NCI/CADD Identifier FICTS FICu. S • calculation of a set of parent structures with different uuuuu sensitivity to chemical features • representation of chemical structures on different levels NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Unique Representation of Chemical Structures NCI/CADD Structure Identifiers sensitive / not sensitive Fragments Isotopes Charges Tautomers Stereo FICTS FICu. S uuuuu O HN ON NH 2 Na+ 4 A 122 D 094098 B 50 D-FICTS-01 -1 D 0 E 26 B 623 DF 7 FAD 30 -FICu. S-01 -70 9850 FD 9 F 9 E 2 B 4 E 25 -uuuuu-01 -27 <CACTVS hashcode (E_HASHISY)>-<tag>-<version>-<checksum> NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

O O N NH OH HN OH O N NH 2 HN OH N NH 2 stereoisomers tautomer O O HN salt ON charged form Na+ HN NH 2 O OH N NH 2 HN O- N NH 3+ histidine isotope “errors” O HN O N NH 2 O O Na HN OH N NH OH N 15 NH 2 NH NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

O O N NH OH HN OH NH 2 N NH 2 HN E 92 E 4 BA 2869 F 3611 -FICTS 6 C 16 DE 2351 F 9 FF 50 -FICTS O stereoisomers tautomer OH N NH 2 8 A 7 AD 1 EB 498 CC 76 A-FICTS O O HN salt ON charged form Na+ HN NH 2 O N NH 2 E 5 F 83 F 10 C 5 DB 080 A-FICTS N NH 3+ isotope “errors” O O- A 3 DAE 0788050 DDE 4 -FICTS 9850 FD 9 F 9 E 2 B 4 E 25 -FICTS HN HN histidine E 5 F 83 F 10 C 5 DB 080 A-FICTS O OH O O Na HN OH N NH NH OH N 15 NH 2 B 2 FDA 68 AEDA 06 DB 9 -FICTS 9850 FD 9 F 9 E 2 B 4 E 25 -FICTS NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

O O N NH OH HN OH NH 2 N NH 2 HN E 92 E 4 BA 2869 F 3611 -FICu. S 9850 FD 9 F 9 E 2 B 4 E 25 -FICu. S O stereoisomers tautomer OH N NH 2 8 A 7 AD 1 EB 498 CC 76 A-FICu. S O O HN salt ON charged form Na+ HN NH 2 O N NH 2 E 5 F 83 F 10 C 5 DB 080 A-FICu. S N NH 3+ isotope “errors” O O- A 3 DAE 0788050 DDE 4 -FICu. S 9850 FD 9 F 9 E 2 B 4 E 25 -FICu. S HN HN histidine E 5 F 83 F 10 C 5 DB 080 A-FICu. S O OH O O Na HN OH N NH NH OH N 15 NH 2 B 2 FDA 68 AEDA 06 DB 9 -FICu. S 9850 FD 9 F 9 E 2 B 4 E 25 -FICu. S NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

O O N NH OH HN OH NH 2 N NH 2 HN 9850 FD 9 F 9 E 2 B 4 E 25 -uuuuu O stereoisomers tautomer OH N NH 2 9850 FD 9 F 9 E 2 B 4 E 25 -uuuuu O O HN ON charged form salt Na+ HN NH 2 O N NH 2 9850 FD 9 F 9 E 2 B 4 E 25 -uuuuu N NH 3+ isotope “errors” O O- 9850 FD 9 F 9 E 2 B 4 E 25 -uuuuu HN HN histidine 9850 FD 9 F 9 E 2 B 4 E 25 -uuuuu O OH O O Na HN OH N NH NH OH N 15 NH 2 9850 FD 9 F 9 E 2 B 4 E 25 -uuuuu 9850 FD 9 F 9 E 2 B 4 E 25 -FICu. S NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

O O N NH OH HN OH NH 2 N NH 2 stereoisomers tautomer OH HN HNDVDQJCIGZPNO-RXMQYKEDSA-N HNDVDQJCIGZPNO-UHFFFAOYSA-N O N NH 2 HNDVDQJCIGZPNO-YFKPBYRVSA-N O O HN salt ON charged form Na+ HN NH 2 O N UHPNKBYGGMJTIM-UHFFFAOYSA-M NH 3+ O O Na NH 2 N isotope “errors” O O- HNDVDQJCIGZPNO-UHFFFAOYSA-N Std. In. Ch. IKey HN HN histidine UHPNKBYGGMJTIM-UHFFFAOYSA-M O OH HN OH N NH NH OH N 15 NH 2 HNDVDQJCIGZPNO-CDYZYAPPSA-N HNDVDQJCIGZPNO-UHFFFAOYSA-N NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Structure Normalization original record original record original record 119. 8 million original structure records in CSDB NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Structure Normalization original record FICTS original record FICTS original record 83. 1 million FICTS parent structures 119. 8 million original structure records in CSDB NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Structure Normalization original record FICTS FICu. S original record FICTS original record 83. 1 million FICTS parent structures 81. 6 million FICu. S parent structures 119. 8 million original structure records in CSDB NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Structure Normalization original record FICTS FICu. S uuuuu original record FICTS FICu. S original record FICTS original record 83. 1 million FICTS parent structures 81. 6 million FICu. S parent structures 76. 2 million uuuuu parent structures 119. 8 million original structure records in CSDB NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Structure Normalization original record FICTS FICu. S uuuuu original record FICTS FICu. S original record FICTS original record 83. 1 million FICTS parent structures 119. 8 million original structure records in CSDB NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space 81. 6 million FICu. S parent structures 76. 2 million uuuuu parent structures tautomerinvariant U. S. Government Chemical Databases and Open Chemistry

Tautomer Analysis How much “chemical space” is “just generated” by drawing tautomers? NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Tautomer Analysis • CACTVS: generation of all formal tautomers for a given organic compound (prototropic tautomerism) • rule set of 21 transforms encoded as (CACTVS-extended) SMIRKS • rule set is systematically applied to the original structure (and all tautomers that have been generated in previous steps) • tautomer generation is limited to 1000 SMIRKS transform operations/structure • all tautomers are ranked by a scoring function • the highest ranked tautomer is defined as the canonical tautomer NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Tautomer Analysis • 21 SMIRKS transform rules: rule 1: 1. 3 (thio)keto/(thio)enol rule 2: 1. 5 (thio)keto/(thio)enol rule 3: simple (aliphatic) imine rule 4: special imine rule 5: 1. 3 aromatic heteroatom H shift rule 6: 1. 3 heteroatom H shift rule 7: 1. 5 (aromatic) heteroatom H shift (1) rule 8: 1. 5 aromatic heteroatom H shift (2) rule 9: 1. 7 (aromatic) heteroatom H shift rule 10: 1. 9 (aromatic) heteroatom H shift rule 11: 1. 11 (aromatic) heteroatom H shift NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space rule 12: furanones rule 13: keten/ynol exchange rule 14: ionic nitro/aci-nitro rule 15: pentavalent nitro/aci-nitro rule 16: oxim/nitroso rule 17: oxim/nitroso via phenol rule 18: cyanic/iso-cyanic acids rule 19: formamidinesulfinic acids rule 20: isocyanides rule 21: phosphonic acids U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Tautomer Analysis FICu. S starting from the set of FICu. S parent structures we systematically generated all tautomers based on the 21 SMIRKS rule set available in CACTVS FICu. S generated 680 million tautomers FICu. S 70. 6 million FICu. S parent structures (2009 DB version) for 1. 7% of the FICu. S parent structures the enumeration was not exhaustive NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Tautomer Analysis tautomeric overlap within each individual database release (%) 90 80 70 number database releases 60 50 frequency 40 30 20 10 0 0. 5 1. 0 1. 5 2. 0 average: ~0. 3% of original structure records NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Tautomer Analysis Asinex Chem. Bridge Com. Genex Chem. Navigator Columbia University Molecular Screening Center number EPA DSSTox database Specs releases Ambinter BIND Binding. DB Chem. Navigator KEGG overlap within tautomeric NCI Open Database NIST Web. Book NLM Chem. IDplus 90 NMRShift. DB Thomson Pharma 80 Wombat 70 each individual database release (%) 60 50 NCI/DTP PASS Training Set SGC-Ox frequency 40 Chem. DB ZINC 30 20 Ch. EBI Chem. Spider 10 0 0. 5 1. 0 1. 5 2. 0 average: ~0. 3% of original structure records NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Tautomer Analysis occurrence of “tautomerism-critical” molecules within each individual database release (%) 30 25 20 number database releases frequency 15 10 5 0 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 average: ~9. 5% of FICu. S parent structures percentage of FICu. S parent structure in each database release occurring somewhere in CSDB with a conflict NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Example for a Tautomer “Conflict” HPMBP (1 -Phenyl-3 -methyl-4 -benzoyl-pyrazolone-5) O HN N O • HPMBP is used in liquid membranes (selective removal of metal ions) • selectivity and efficiency depends on the tautomeric form of HPMBP which itself depends on solvent and concentration of HPMBP He, D. ; Li Z. ; Ma M. ; Huang J. ; Yang Y. Study of extraction characteristics of HPMBP. 1. Tautomer and extraction characteristics. J. Chem. Eng. Data 2009, 54(10), 2944 -2947 NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Example for a Tautomer “Conflict” HPMBP (1 -Phenyl-3 -methyl-4 -benzoyl-pyrazolone-5) O N N OH O O R/S N N O canonical tautomer by CACTVS HN N CACTVS generates 7 tautomers O 5 tautomers have potential stereo center on atoms or bonds N N O R/S OH OH E/Z HN N O NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space HN N OH O R/S HN N O U. S. Government Chemical Databases and Open Chemistry

Example for a Tautomer “Conflict” HPMBP (1 -Phenyl-3 -methyl-4 -benzoyl-pyrazolone-5) O N N OH 33064 -14 -1 49 references O O R/S N N O HN N O 3 tautomers have CAS Registry Numbers assigned 4551 -69 -1 859 references (no stereo) N N O R/S OH OH E/Z HN N OH O R/S HN N O 127117 -31 -1 3 references (Z) NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Example for a Tautomer “Conflict” HPMBP (1 -Phenyl-3 -methyl-4 -benzoyl-pyrazolone-5) O N N OH 12 databases O O R/S N N O 16 databases (no stereo) 3 databases (R) 2 databases (S) HN N 6 databases N O R/S OH OH E/Z N O occurrences in databases indexed in CSDB HN N OH O R/S HN N O 1 database (no stereo) NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Example for a Tautomer “Conflict” HPMBP (1 -Phenyl-3 -methyl-4 -benzoyl-pyrazolone-5) O O O R/S N N OH 12 databases ACD 3 D Ambinter Binding. DB Chem. Bank Chem. DB Chem. Spider Chem. Navigator MLSMR NIAID Scripps Screening Center Thomson Pharma ZINC N N HN O 16 databases (no stereo) 3 databases (R) 2 databases (S) OH Chem. Spider ZINC N N N 6 databases Chem. Spider ECOTOX ZINC OH E/Z O O HN N O NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space Ambinter Chem. DB Chem. Spider occurrences in databases Discovery. Gate Chem. Navigator Thomson Pharma ACD 3 D ACX Ambinter Bio. Byte QSAR Chem. Bank Chem. Bridge Chem. DB Chem. Spider R/S Discovery. Gate OH EPA GCES MLSMR HN OH N NCI Open Database NIST MS-Lib NLM Chem. IDplus Sigma-Aldrich Thomson Pharma Chem. DB O R/S HN N O 1 database (no stereo) U. S. Government Chemical Databases and Open Chemistry

Scaffold Analysis NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Scaffold Analysis level 1 level 2 O N NH O example N NH molecular scaffold tree Schuffenhauer et al. J. Chem. Inf. Model. 2007, 47 -58 O N NH O S O simple scaffold Bemis et al. J. Med. Chem. 1996, 39, 2887 -2893 archetype scaffold Bemis et al. J. Med. Chem. 1996, 39, 2887 -2893 NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Scaffold Analysis CSDB uuuuu compound set 76. 2 million NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Scaffold Analysis level 2 molecular scaffold tree O N level 1 NH O 8. 1 million scaffolds N NH CSDB uuuuu compound set simple scaffold N NH 6. 8 million scaffolds 76. 2 million archetype scaffold 0. 8 million scaffolds NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Scaffold Analysis level 2 number of unique scaffolds per hierarchy level O molecular scaffold tree N NH O 8. 1 million scaffolds 76. 2 million Number of Unique Scaffolds (in millions) uuuuu compound set 8. 0 80. 0 70. 0 60. 0 50. 0 40. 0 30. 0 20. 0 10. 0 0 N NH Number of unique structures (in million) CSDB level 1 0 1 2 3 4 5 6 7 8 9 10 Hierarchy Level NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Atom Neighborhoods NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Multilevel Neighborhoods of Atoms (MNA) MNA level 1 H N H OH O HC HO CHCC CHCN CCCC CCOO NCC OHC OC MNA level 2 C(C(CC-H)C(CC-C)-H(C)) C(C(CC-H)C(CN-H)-C(C-O-O)) C(C(CC-H)N(CC)-H(C)) C(C(CC-C)N(CC)-H(C)) N(C(CN-H)) -H(C(CC-H)) -H(C(CN-H)) -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)) Filimonov D. , Poroikov V. , Borodina Yu. , Gloriozova T. J. Chem. Inf. Comput. Sci. , 1999, 39 (4), 666 -670. NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Multilevel Neighborhoods of Atoms (MNA) CSDB uuuuu compound set 76. 2 million NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Multilevel Neighborhoods of Atoms (MNA) Unique MNAs CSDB level 1 13, 426 level 2 918, 516 uuuuu compound set 76. 2 million NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Multilevel Neighborhoods of Atoms (MNA) Unique MNAs CSDB uuuuu compound set 76. 2 million 1. 3 billion relationships level 1 13, 426 level 2 918, 516 ~ 17 MNAs per uuuuu parent structure 2. 3 billion relationships ~ 30 MNAs per uuuuu parent structure NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Structure Database Multilevel Neighborhoods of Atoms (MNA) Unique MNAs CSDB uuuuu compound set 76. 2 million 1. 3 billion relationships level 1 13, 426 level 2 918, 516 ~ 17 MNAs per uuuuu parent structure 2. 3 billion relationships ~ 30 MNAs per uuuuu parent structure surprising: 424, 784 MNAs (level 2) are exclusive to a set of 1, 3 million structures in Chem. Spider NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Web Resources Chemical Structure Web Services Chemical Identifier Resolver NCI/CADD web service external (web) services NCI/CADD web service http Chemical Structure Web Services CACTVS NCI/CADD Chemical Structure Database (CSDB) NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space other software packages e. g. OPSIN U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Web Resources Chemical Identifier Resolver avogadro. openmolecules. net/ Symyx Draw Resolver http: //www. akosgmbh. eu/globalsearch/index. htm http: //www. symyx. com/ webel. py - A Cinfony module http: //baoilleach. blogspot. com/2009/11/ introducing-webel-cheminformatics. html g. Chem Virtual Molecular Model Kit http: //chemagic. com/web_molecules/script_page_large. aspx CACTVS http: //www. xemistry. com NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space IUPHAR DATABASE http: //www. iuphar-db. org U. S. Government Chemical Databases and Open Chemistry

Work in progress … Chemical Structure Lookup Service II NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Work in progress … Chemical Structure Lookup Service II NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Acknowledgments Thanks to all database providers! CADD Group, CBL, NCI Igor Filippov University of Cambridge Daniel Lowe Peter Murray-Rust Chem. Navigator Scott Hutton Tad Hurst Chem. Spider Antony Williams Valery Tkachenko Noel’ O Boyle (University College Cork, Ireland) Richard Apodaca (Metamolecular) Hans-Juergen Himmler Our web site: http: //cactus. nci. nih. gov NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Web Resources Chemical Identifier Resolver http: //cactus. nci. nih. gov/chemical/structure http: //cactus. nci. nih. gov/blog NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

Acknowledgments - Software CACTVS Chem. Writer Peter Ertl Python Web Framework Python SQL library Javascript library NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry

NCI/CADD Chemical Identifier Resolver: Indexing and Analysis of Available Chemistry Space U. S. Government Chemical Databases and Open Chemistry