Chemical Databases, Identifiers, Tool Kits and Web Services October 16, 2003

1. Chemical Databases, Identifiers, Tool Kits and Web ServicesOctober 16, 2003 Marc C. Nicklaus, CADD Group, Lab. of Medicinal Chemistry, CCR, NCI, NIH; mn1@helix.nih.gov Thanks also to the other members of the CADD Group: Rajeshri G. Karki, Megan L. Peach, Karen M. Green, Guangyu Sun, Igor Filippov

2. Acknowledgements • Wolf-Dietrich Ihlenfeldt (formerly Computer Chemistry Center [CCC], Erlangen, Germany) • Frank Oellien (formerly CCC) • Bruno Bienfait (formerly CCC and LMC) • Johannes Voigt (formerly LMC)

3. Reasons to Deal with (Large) Chemical Databases (of Small Molecules) • Inventory • Source for drug design, (virtual) screening • Repository for associated information (assay results, physicochemical data, environmentally important properties etc.) • Chemoinformatics • Link to other services, databases • Source for individual structures (e.g. for comp. chem.)

4. Questions • What databases are out there? • What databases can we share? • What tools can we share? • What can we offer the public? • [How] Can we standardize? • How can we determine: have we, has anyone, see this structure before? • What’s next (XML/CML… )?

5. The NCI Database & Enhanced NCI Database Browser

6. The NCI Database • Approximately half a million compounds • Collected since 1955 by the National Cancer Institute, NIH • Tested in anti-cancer screens; since 80’s also in AIDS screens • Managed by NCI’s Developmental Therapeutics Program (DTP); see http://dtp.nci.nih.gov • Publicly available: currently 260,071 cpds. (“Open NCI Database”) • Cancer screening data (60 cell lines) available for ca. 43,000 compounds • AIDS screening data available for ca. 44,000 compounds • Samples available from DTP for ~60% of compounds

7. Enhanced CACTVS Browser of the Open NCI Database • Web-based interface for searching data from the Open NCI Database by numerous criteria, including 2D and 3D structural searches • Augmented by many additional data, - derived: e.g. number of rotatable bonds - calculated/predicted: e.g. log P; biological activities - systematically determined: e.g. IUPAC names - cross-evaluated: e.g. commercial availability • Boolean searches possible • Requirements: Just a Web browser, several plug-ins are optional • Based on chemical information toolkit CACTVS (Wolf-Dietrich Ihlenfeldt, see http://www2.chemie.uni-erlangen.de/software/cactvs/)

8. How To Get There…. URLs: http://cactus.nci.nih.gov/ncidb2 (U.S. mirror) http://www2.chemie.uni-erlangen.de/ncidb2 (European mirror)

9. http://cactus.nci.nih.gov

10. Enhanced NCI Database Browser: Query Form

11. Combined Search: PASS Antiangiogenesis Prediction & Name (Fragment) Exclusion

12. Search Result: Hitlist

13. Search Result: Image Gallery

14. Search Result: Detail View (top)

15. Search Result: Detail View (continued)

17. Update of Enhanced NCI Database Browser • Most up-to-date DTP data sets • Completion/curation of data where possible • Many more additional calculated data • New search capabilities • New underlying database format

18. Update of Enhanced NCI Database BrowserMost up-to-date DTP data sets • 260,071 compounds (new and old releases of Open NCI Database merged, new entry prevails) • 42,577: have cancer screen results >300 properties • 43,905: have AIDS screening results 3 (EC50: 3,143; IC50: 39,352) • 115,324: have animal model assay data (NEW) ~10 (string) • 139,735: are plated 1 • 45,224: have name(s) (from DTP records) 0...>20 • 127,361: have CAS RN 1 • 3,576: have experimental log P 1

19. Update of Enhanced NCI Database BrowserCompletion/curation of data • Add CAS numbers: cross-check with other DBs • Correct structures and/or names: mostly manually, only occasionally possible, often dangerous • Calculate averages and SD for cell-line assay data • (No evaluation/curation planned for animal model assay data)

20. Download Page http://cactus.nci.nih.gov/ncidb2/download.html 260,071 2D or 3D structures with USMILES, IChI, IUPAC Name, CAS RN and additional “canonical properties” [in beta test stage: http://cactus.nci.nih.gov/ncidb2/download_NEW_09-03.html ] 250,251 2D structures in SDF format 250,251 structures in USMILES format 249,081 2D structures plus cancer and AIDS data (where present) in SDF format 32,557 2D structures with cancer test data as of August 1999, in SDF format 42,689 2D structures with AIDS test data as of October 1999, in SDF format 23,031 2D structures in SDF format for which both cancer and AIDS data are available Updated structure and combined structure+data files under preparation

21. Future Plans and Wishes… • Apply/add IChI names • Create Search&Display GUIs for more DBs • Cross-complete databases (CAS RNs etc.) • XML/CML-ize databases • Move toward one virtual chemical database • Link different database spaces together (small molecules, macromolecules, toxicity data, comp.chem. data, spectral data, patent data…)

22. Other Databases

23. Public U.S. Government Chemical Databases NCI Open (02/03) 260,017 NIST WebBook (04/03) 31,167 NLM ChemIDplus (04/03) 160,590 EPA GCES Database (03/02) 66,347 Combined USGovtPubDB ~515,000 More will hopefully follow from: NIAID, EPA, FDA…

24. Databases U.S. Government Databases NCI Open (09/03) 260,071 public NIST MS Library (2002) 147,194 NIST WebBook (04/03) 31,167 public NLM ChemIDplus (04/03) 160,590 public EPA GCES Database (03/02) 66,347 public Commercial/Other Databases ACD (1.1999) 221,668 ACX (1999) 137,003 Ambinter (08/02) 487,397 Asinex Gold (09/03) 202,237 Asinex Platinum (09/03) 117,518 Beilstein Natural Products (02/02) 124,701 ChemBridge (02/02) 100,000 ChemDiverse IDC (09/03) 122,684 ChemDiverse CombiLab (09/03) 201,139 ChemNavigator (08/03) 6,954,906 ChemStar (05/03) 72,407 Petrenko (PN07) 115,554 Ryan (10/02) 294,437 Sigma-Aldrich Rare Chem. (08/02) 124,728 CSD (5.24, 11/02, organic only) 103,860

25. Canonical Version • Hydrogens added • 3D coordinates calculated • Some deficiencies fixed (nitro groups…) • Canonical property fields added • Original fields (mostly) left untouched • Not yet done, but possible: completed data, e.g. CAS RN, name etc.

26. SD Files: NOT Standardized! Fields: ID Chem. Name Rec# CAS RN Formula MDL Name (first line) Database:Field Names: NCI Open (02/03) NSC - - - - NSC (id) NIST MS Library (2002) ID - - - - - NIST WebBook (04/03) WEBBOOK.ID NAME (n) <...> CAS.NUMBER FORMULA (name) [, ID: (id)] NLM ChemIDplus (04/03) ID molname - - - EPA GCES Database (03/02) (**came as list of SMILES strings** ACD (1.1999) NAME (1st rec.) (n) <...> - - (name) ACX (1999) CsNum - <...> (n) CAS Formula “MDL Molfile” Ambinter : File 0 ID - IDNUMBER - - - File 1 id - IDNUMBER - - - File 2 idnumber - ID - - (id) File 3 Code - ID - - - Asinex Gold (06/03) IDNUMBER - - - - - Asinex Platinum (06/03) IDNUMBER - - - - - Beilstein Natural Products (02/02) BRN CN ID RN - - ChemBridge (02/02) ID - - - - - ChemDiverse IDC (04/03) IDNUMBER - - - - - ChemDiverse CombiLab (04/03) IDNUMBER - - - - - ChemNavigator (06/03) CNC_ID - - - - (id) ChemStar (05/03) IDNUMBER - - - - - Petrenko (PN07) id - - - - - Ryan (10/02) code name ID - - - Sigma-Aldrich Rare Chem. (08/02) CAT_NO - - - - - World Drug Index (3.1999) [RNEXTREG] MOLNAME(1) - CAS MF (name) (1) Possibly, but not consistently, repeated in fields <RNEXTREG> and/or <RN>

27. Canonical Fields Field/Property Name Possible values (or explanation) Properties dependent on structure: E_UNIQUE_ID to be concatenated from Origin + Version/Date + internal ID; example: NLM_04-03_08359076 E_CAS CAS Reg. No. (if available; otherwise 999-99-9) E_NAME Chemical Name (if available) E_STEREO_SPECIFIED no_stereocenter | unknown | partial | full (for most DBs, only choices 1 & 4 relevant) E_COMPOUND_TYPE unspecified (i.e. typically “normal organic”) metal_complex (if pre-processed as such) .... (maybe others?) E_THREED_SOURCE is_2D | experimental | CORINA_x.y | 3D_unsuccessful E_ICHI IChI chemical identifier E_SMILES CACTVS-calculated Unique SMILES code (according to 1989 definition published by Daylight, Inc.) E_FORMULA Molecular formula calculated by CACTVS E_HASHY Non-stereospecific hash code E_HASHSY Stereospecific hash code E_TAUTO_HASH Non-stereospecific tautomer-invariant hash code E_STEREO_TAUTO_HASH Stereospecific tautomer-invariant hash code E_MAXFRAG_HASHY Non-stereospecific hash code of largest fragmnet E_MAXFRAG_HASHSY Stereospecific hash code of largest fragmnet E_MAXFRAG_HASHTY Non-stereospecific tautomer-invariant hash code of largest fragmant E_MAXFRAG_HASHSTY Stereospecific tautomer-invariant hash code of largest fragmant E_MULTIFRAG single_fragment | multi_fragment Properties constant for whole database: E_ORIGIN Detailed origin of data file; e.g. “DTP February 2003” E_DB_VERSION Explicit DB version number, if available E_DB_YEAR Year data file was generated E_DB_TYPE government public (e.g. NCI Open DB) government non-public (e.g. NIST WebBook) commercial free (e.g. Sig.-Al. RCL) commercial licensed (e.g. CSD, WDI, ACD...) E_IS_PUBLIC yes | no | unknown E_SAMPLES_AVAIL yes | on-demand | no | unknown (for whole DB!) E_SOURCE Source of database: Company, Agency etc.; e.g. “NCI” E_CONTEXT Nature, or context, of compound: e.g. environmentally relevant cpd., general chemical, drug… E_SUPPLIER_TYPE broker | manufacturer | repository / N/A E_CACTVS_VERSION x.yyy (version of the CACTVS toolkit used to process the database)

28. Can’t we all get along with each other? 

29. Identifiers

30. CACTVS Hash Codes

31. Overlap Analysis via Hash Codes • CACTVS hash codes • Tautomer-invariant hash codes (NEW!) • Stereospecific vs. non-stereospecific, tautomer-sensitive vs. tautomer-invariant, entire ensemble vs. max. fragment only, -- all eight combinations calculated and added to SD file. • Index file created for rapid comparison:

32. Hash Codes

33. Index File 009F2C8EFECD9E45 009F2C8EFECD9E45 000140-95-4 EPA_GCES_03-02_000140-95-4 C3H8N2O3 009F2C8EFECD9E45 009F2C8EFECD9E45 025155-29-7 EPA_GCES_03-02_025155-29-7 C3H8N2O3 009F2C8EFECD9E45 009F2C8EFECD9E45 140-95-4 NIST_WebBook_04-03_C140954 C3H8N2O3 009F2C8EFECD9E45 009F2C8EFECD9E45 25155-29-7 NIST_WebBook_04-03_C25155297 C3H8N2O3 009F2C8EFECD9E45 009F2C8EFECD9E45 ChemStar_05-03_CHS_0025004 C3H8N2O3 009F2C8EFECD9E45 009F2C8EFECD9E45 NIST_MS-Lib_02_140954 C3H8N2O3 0106B6B3BC4B9B7C 0106B6B3BC4B9B7C AsinexGold_06-03_BAS_0605175 C15H12N2O2 0106B6B3BC4B9B7C 0106B6B3BC4B9B7C ChemStar_05-03_CHS_0816990 C15H12N2O2 0106B6B3BC4B9B7C 0106B6B3BC4B9B7C NIST_MS-Lib_02_304480737 C15H12N2O2 0106B6B3BC4B9B7C 0106B6B3BC4B9B7C PN07_10-02_PN07_025090 C15H12N2O2 056832FA004D9ED0 056832FA004D9ED0 ?? 010118-90-8 EPA_GCES_03-02_010118-90-8 C23H27N3O7 056832FA004D9ED0 056832FA004D9ED0 ?? NIST_MS-Lib_02_10118908 C23H27N3O7 SMILES code appended to each line (not shown here) Very rapid searches, overlap analyses, counts etc. with just Unix pipes.

34. IChI

35. with permission of Steve Stein… The IUPAC Chemical Identifier Steve Stein, Steve Heller, Dmitrii Tchekhovskoi National Institute of Standards and Technology Gaithersburg, MD, USA U.S. Government Chemical Databases Frederick, MDJuly 22, 2003

36. Too Many Identifiers • Structure diagrams • various conventions • contain ‘too much’ information • Connection Tables • MolFiles, Smiles, ROSDAL, .. • Pronounceable names • IUPAC, CAS, trivial • Index Numbers • EINECS, FEMA, DOT, RTECS, CAS, Beilstein, USP, RTECS, EEC, RCRA, NCI, UN, USAF

37. What kind of Identifier is needed? • Derived from structure by algorithm • Accepts common drawing conventions • Exactly one Identifier per structure • Comprehensive • Openly available

38. Requirements • Different compounds have different identifiers • All distinguishing structural information is included = = IChI - 2 IChI - 1

39. Requirements • One compound has only one identifier • Include only necessary information = = = Same IChI

40. IChIFirst Version • Discrete, bonded compounds • Include ‘dot disconnected’ compounds • Stereochemistry • sp3 - tetrahedral • Z/E - double bond • Tautomers

41. 3 Steps to IChI • ‘Normalize’ Input Structure • Defined input structure required • Remove conventions with chemical rules • Divide into ‘layers’ • ‘Canonicalize’ (label the atoms) • Equivalent atoms get the same label • ‘Serialize’ the Labeled Structure • A unique series of bytes

42. Simplifications • Ignore ‘Electron Density’ • Double/Triple/Coordination bonds • Odd-electrons/Charges • Free Rotation Around Single Bonds • Separate structure information into ‘layers’

44. Output Format Example: Benzene Represent atoms as sequence number in formula C6H6   = C  C  C  C  C  C  H  H  H  H  H H      tags 1  2  3  4   5   6   7  8   9 10 11 12 Basic Layer: <basic>C6H6 1-2-7 2-3-8 3-4-9 4-5-10 5-6-11 7-12</basic>

45. <IChI version="0.933Beta"> <structure number="1" id.name="Name" id.value="Monosodium glutamate"> <identifier version="0.933Beta" tautomeric="1"> <formula>C5H8NO4.Na</formula> <connections>6H2-5H(4(9)10)2H2-1H2-3(7)8,(H-,7,8,9,10);</connections> <charge>-1;+1</charge> <stereo> <dbond>;</dbond> <sp3>5?;</sp3> </stereo> </identifier> </structure> </IChI>

46. Disconnected Connected <IChI version="0.933Beta"> <structure number="1" id.name="Name" id.value="Ferrocene"> <identifier version="0.933Beta" tautomeric="0" disconnected="1"> <formula>C5H5.C5H5.Fe</formula> <connections>1H-2H-4H-5H-3H-1;1H-2H-4H-5H-3H-1;</connections> <charge>-1;-1;+2</charge> <reconnected> <formula>C10H10Fe</formula> <connections>1H-2H-4H-5H-3H(1)11(1,2,4,5)6H-7H(11)9H(11)10H(11)8H(6)11</connections> <charge></charge> </reconnected> </identifier> </structure> </IChI>

47. Future Extensions • Other Stereo Forms • Non-atom centered • Conformations • Hydrogen Bonding • Polymers/Macromolecules • Compound Classes • Markush structures

48. Tools

49. Tools • CACTVS • Pipeline Pilot • MDL Software • Daylight Software • Oracle • Others…

50. Free Tools • CACTVS Scripts; GUI-based tools; Web services; free for academic and public use. Unix, Linux. • GUI Generator Generate Web interface automatically from SD file and data. CACTVS- based. Free for non-profit use. Under development.