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

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)

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.)

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… )?

The NCI Database &

Enhanced NCI Database Browser

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

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/)

How To Get There….

URLs: http://cactus.nci.nih.gov/ncidb2

(U.S. mirror)

http://www2.chemie.uni-erlangen.de/ncidb2

(European mirror)

http://cactus.nci.nih.gov

Enhanced NCI Database Browser: Query Form

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

Search Result: Hitlist

Search Result: Image Gallery

Search Result: Detail View (top)

Search Result: Detail View (continued)

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

Update of Enhanced NCI Database Browser

Most 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

Update of Enhanced NCI Database Browser

Completion/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)

Download Pagehttp://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 format250,251 structures in USMILES format249,081 2D structures plus cancer and AIDS data (where present) in SDF format32,557 2D structures with cancer test data as of August 1999, in SDF format42,689 2D structures with AIDS test data as of October 1999, in SDF format23,031 2D structures in SDF format for which both cancer and AIDS data are

available

Updated structure and combined structure+data files under preparation

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…)

Other Databases

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…

DatabasesU.S. Government Databases

NCI Open (09/03) 260,071 publicNIST MS Library (2002) 147,194NIST WebBook (04/03) 31,167 publicNLM ChemIDplus (04/03) 160,590 publicEPA GCES Database (03/02) 66,347 public

Commercial/Other DatabasesACD (1.1999) 221,668ACX (1999) 137,003Ambinter (08/02) 487,397Asinex Gold (09/03) 202,237Asinex Platinum (09/03) 117,518Beilstein Natural Products (02/02) 124,701ChemBridge (02/02) 100,000ChemDiverse IDC (09/03) 122,684ChemDiverse CombiLab (09/03) 201,139ChemNavigator (08/03) 6,954,906ChemStar (05/03) 72,407Petrenko (PN07) 115,554Ryan (10/02) 294,437Sigma-Aldrich Rare Chem. (08/02) 124,728CSD (5.24, 11/02, organic only) 103,860

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.

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>

Canonical FieldsField/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_08359076E_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_unsuccessfulE_ICHI IChI chemical identifierE_SMILES CACTVS-calculated Unique SMILES code (according to 1989 definition published by Daylight, Inc.)E_FORMULA Molecular formula calculated by CACTVSE_HASHY Non-stereospecific hash codeE_HASHSY Stereospecific hash codeE_TAUTO_HASH Non-stereospecific tautomer-invariant hash codeE_STEREO_TAUTO_HASH Stereospecific tautomer-invariant hash codeE_MAXFRAG_HASHY Non-stereospecific hash code of largest fragmnetE_MAXFRAG_HASHSY Stereospecific hash code of largest fragmnetE_MAXFRAG_HASHTY Non-stereospecific tautomer-invariant hash code of largest fragmantE_MAXFRAG_HASHSTY Stereospecific tautomer-invariant hash code of largest fragmantE_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 availableE_DB_YEAR Year data file was generatedE_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 | unknownE_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/AE_CACTVS_VERSION x.yyy (version of the CACTVS toolkit used to process the database)

Can’t we all get along with each other?

Identifiers

CACTVS Hash Codes

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:

Hash Codes

Index File009F2C8EFECD9E45 009F2C8EFECD9E45 000140-95-4 EPA_GCES_03-02_000140-95-4 C3H8N2O3009F2C8EFECD9E45 009F2C8EFECD9E45 025155-29-7 EPA_GCES_03-02_025155-29-7 C3H8N2O3009F2C8EFECD9E45 009F2C8EFECD9E45 140-95-4 NIST_WebBook_04-03_C140954 C3H8N2O3009F2C8EFECD9E45 009F2C8EFECD9E45 25155-29-7 NIST_WebBook_04-03_C25155297 C3H8N2O3009F2C8EFECD9E45 009F2C8EFECD9E45 ChemStar_05-03_CHS_0025004 C3H8N2O3009F2C8EFECD9E45 009F2C8EFECD9E45 NIST_MS-Lib_02_140954 C3H8N2O3

0106B6B3BC4B9B7C 0106B6B3BC4B9B7C AsinexGold_06-03_BAS_0605175 C15H12N2O20106B6B3BC4B9B7C 0106B6B3BC4B9B7C ChemStar_05-03_CHS_0816990 C15H12N2O20106B6B3BC4B9B7C 0106B6B3BC4B9B7C NIST_MS-Lib_02_304480737 C15H12N2O20106B6B3BC4B9B7C 0106B6B3BC4B9B7C PN07_10-02_PN07_025090 C15H12N2O2

056832FA004D9ED0 056832FA004D9ED0 ?? 010118-90-8 EPA_GCES_03-02_010118-90-8 C23H27N3O7056832FA004D9ED0 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.

IChI

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

with permission of Steve Stein…

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

What kind of Identifier is needed?

• Derived from structure by algorithm

• Accepts common drawing conventions

• Exactly one Identifier per structure

• Comprehensive

• Openly available

Requirements

• Different compounds have different identifiers– All distinguishing structural information is included

IChI - 1 IChI - 2=

=

Requirements

• One compound has only one identifier– Include only necessary information

NOO

NOO

N+ OO

NOO

Same IChI

= ==

IChIFirst Version

• Discrete, bonded compounds– Include ‘dot disconnected’ compounds

• Stereochemistry– sp3 - tetrahedral

– Z/E - double bond

• Tautomers

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

Simplifications

• Ignore ‘Electron Density’– Double/Triple/Coordination bonds– Odd-electrons/Charges

• Free Rotation Around Single Bonds

• Separate structure information into ‘layers’

NOO

N+O O

NOO

H

H

H

H

H

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>

C3 C4

O7

CH2

1

O9

CH2

2

CH5 OH

10O

8

NH26Na

+1

<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>

CH1

CH2

CH3

CH5

CH4

CH1

CH2

CH4

CH5

CH3

Fe2+1

CH1

Fe2+11

CH2

CH-3

CH5

CH4

CH6

CH-7

CH9

CH10

CH8

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>

Future Extensions

• Other Stereo Forms– Non-atom centered– Conformations– Hydrogen Bonding

• Polymers/Macromolecules

• Compound Classes– Markush structures

Tools

Tools

• CACTVS

• Pipeline Pilot

• MDL Software

• Daylight Software

• Oracle

• Others…

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.

http://www2.ccc.uni-erlangen.de/software/cactvs/tools.html

CACTVS Documentation

The most complete documentation for CACTVS as of now resides on the LMC Intranet server. Please contact me (mn1@helix.nih.gov) for info.

Web Services

Additional Links and Information

Other Public Chemical Data A list of URLs that point to other public chemical (or chemistry-

related) information. Currently limited to U.S. Government web sites. These sites may contain search capabilities and/or other public datasets:

http://cactus.nci.nih.gov/ncidb2/govt_dbs.html

Chemistry Search Services on the Web A table of searchable small molecule databases available on the web,

listing URLs and an (incomplete) survey of the services' features and capabilities.

Contains (U.S.) Government, academic, and commercial web sites:

http://cactus.nci.nih.gov/ncidb2/chem_www.html

Online SMILES Translatorhttp://cactus.nci.nih.gov/services/translate/

Generate Unique SMILES;Translate Between Formats:SD, PDB, MOL, SMILES

“GIF” Creatorhttp://cactus.nci.nih.gov/services/gifcreator/

Create High-Quality 2D Drawingsof Your Chemical Structures:Many input formats supported:SD, MOL, PBD, SMILES, Sybyl…

NCI Screening Data 3D Minerhttp://cactus.nci.nih.gov/services/3DMiner/

Visualize & Mine 60-Cell Line Cancer Data for 41,000 NCI Compounds

GUI Generator CACTVS-based GUI that takes a structure

file (SD or other format) and associated data files (TXT, Excel, etc.) as input and generates a Web service from it. Its output is a CACTVS database file (.cbase file) and the CACTVS script – generating JavaScript pages – that allows web-based searches and display of results in/from this database.

Will be freely distributed for non-profit use. Since script=executable, also freely adaptable. Currently: alpha version.

Pipeline Pilot

• Scitegic, Inc.• GUI-based Icon Pipeline paradigm• Predefined components (really: scripts); you can

modify, or write your own ones• Drag&drop to form pipelines• Ensemble of pipelines is the program (called

‘Protocol’), can be saved, shared…• Now Win. 2000/XP only; fall ‘03: Linux• Very fast: up to 20,000 cpds/sec• Expensive

3D Pharmacophore Searches• Up to 25 conformers pre-

calculated by the program Catalyst (MSI) are stored for each compound.

• Searches are possible by distance constraints and other query features. Most ISIS features are implemented, such as exclusion spheres, centroids, points on lines….

• There are two ways to define a query: Query file is prepared in an external program, such as Catalyst, ISIS/Draw etc., and submitted in .mol format; or use JME Editor available within the service.

Example:3-Point pharmacophore used in previous study on HIV-1 integrase inhibitor discovery. J.Med.Chem. 1997, 40(6), 920-929.

9.053±0.4Å

8.711±0.4Å

2.548±0.3Å

3D Pharmacophore Search -- Result