Chemicals, Chemical Identifiers and Navigating Through Databases

Chemicals, Chemical Identifiers and Navigating Through Databases

Antony WilliamsUNC Chapel Hill, October 2010

Chemistry on the Internet

Where do you source chemistry information? What can you trust online? How can you recognize potential issues? Cross-referencing and curating data

What is the Structure of Vitamin K?

MeSH

A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: VITAMIN K 1 (phytomenadione) derived from plants, VITAMIN K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, VITAMIN K 3 (menadione). Vitamin K 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin K. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin K

What is the Structure of Vitamin K1?

Wikipedia

What is the Structure of Vitamin K1?

CAS’s Common Chemistry

PubChem

“2-methyl-3-(3,7,11,15-tetramethylhexadec-2-enyl)naphthalene-1,4-dione”

Variants of systematic names on PubChem

2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethyl 2-methyl-3-[(E,7S,11R)-3,7,11,15-tetramethyl 2-methyl-3-[(E,7R,11S)-3,7,11,15-tetramethyl 2-methyl-3-[(E,7S,11S)-3,7,11,15-tetramethyl 2-methyl-3-[(E,11S)-3,7,11,15-tetramethyl 2-methyl-3-[(E)-3,7,11,15-tetramethyl 2-methyl-3-(3,7,11,15-tetramethyl 2-methyl-3-[(E)-3,7,11,15-tetramethyl

Bioassay Data are Associated…

Lack of Stereochemistry

ChEBI – Manual Curation

Molfiles (http://en.wikipedia.org/wiki/Chemical_table_file)

Molfiles 10 9 0 0 1 0 0 0 0 0 1 V2000 31.2937 -9.0366 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 26.6526 -9.0366 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 31.2937 -7.7066 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 30.1161 -9.6877 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 25.5096 -9.6877 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 28.9731 -9.0366 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 27.8163 -9.7016 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 26.6664 -7.7066 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0 32.4367 -9.6877 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 30.1161 -11.0177 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0 3 1 2 0 0 0 0 4 1 1 0 0 0 0 9 1 1 0 0 0 0 7 2 1 0 0 0 0 5 2 2 0 0 0 0 8 2 1 0 0 0 0 6 4 1 0 0 0 0 4 10 1 6 0 0 0 7 6 1 0 0 0 0 M END

Molfiles Molfiles are the primary exchange format between

structure drawing packages Can be different between different drawing packages Most commonly carry X,Y coordinates for layout Can support polymers, organometallics, etc. Can carry 3D coordinates

SMILES (http://en.wikipedia.org/wiki/SMILES)

SMILES is a common format Can support polymers,

organometallics, etc. Does NOT carry X,Y or Z

coordinates for layout so requires layout algorithms – can be problematic!

Generally different between drawing packages

Stereo

Tautomers

SMILES ACD/Labs CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCC(\

C)=C\CC2=C(C)C(=O)c1ccccc1C2=O

OpenEye CC1=C(C(=O)c2ccccc2C1=O)C/C=C(\C)/

CCC[C@H](C)CCC[C@H](C)CCCC(C)C

ChEMBL CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC\

C(=C\CC1=C(C)C(=O)c2ccccc2C1=O)\C

The InChI Identifier

InChI

SINGLE code base managed by IUPAC – integrated into drawing packages. No variability as with SMILES

InChI Strings can be reversed to structures – same problem as with SMILES – no layout

Well adopted by the community (databases, publishers, blogs, Wikipedia) – good for searching the internet

Multiple Layers

Tautomers – “Mobile H Perception”

Double Bond Orientation

Stereo

Checking for Stereochemistry

Checking for StereochemistryUse your drawing package!

Checking for Stereochemistry

Checking for Stereochemistry

Checking for Stereochemistry

InChIStrings Hash to InChIKeys

PubChem InChIKeys

MBWXNTAXLNYFJB-NKFFZRIASA-N MBWXNTAXLNYFJB-LKUDQCMESA-N MBWXNTAXLNYFJB-UHFFFAOYSA-N MBWXNTAXLNYFJB-FAKCLFGASA-N MBWXNTAXLNYFJB-NIHVXYICSA-N (O-18 label) MBWXNTAXLNYFJB-ODDKJFTJSA-N MBWXNTAXLNYFJB-KSVLJPARSA-N MBWXNTAXLNYFJB-UDCSOKOMSA-N MBWXNTAXLNYFJB-JHBCSKSVSA-N MBWXNTAXLNYFJB-JXAKDHTRSA-N

PubChem InChIKeys

MBWXNTAXLNYFJB-NKFFZRIASA-N MBWXNTAXLNYFJB-LKUDQCMESA-N MBWXNTAXLNYFJB-UHFFFAOYSA-N MBWXNTAXLNYFJB-FAKCLFGASA-N MBWXNTAXLNYFJB-NIHVXYICSA-N (O-18 label) MBWXNTAXLNYFJB-ODDKJFTJSA-N MBWXNTAXLNYFJB-KSVLJPARSA-N MBWXNTAXLNYFJB-UDCSOKOMSA-N MBWXNTAXLNYFJB-JHBCSKSVSA-N MBWXNTAXLNYFJB-JXAKDHTRSA-N

Databases and Standardization

Databases and Standardization

InChI

No support for polymers, organometallics

Many option settings can lead to variability and make integration across databases difficult – FixedH option especially problematic

“Slight” chance of collisions of InChIKeys

VERY USEFUL FOR INTEGRATING THE WEB

Vancomycin

Vancomycin

Search Molecular SKELETON

Search Full Molecule

Full Skeleton Search: 104 Hits

Full Molecule Search: 4 Hits

Where is chemistry online? Encyclopedic articles (Wikipedia) Chemical vendor databases Metabolic pathway databases Property databases Patents with chemical structures Drug Discovery data Scientific publications Compound aggregators Blogs/Wikis and Open Notebook Science

Linked Data on the Web

Taken from: Rafael Sidis’ Blog

www.chemspider.com

Search for a Chemical…by name

Available Information…

Linked to vendors, safety data, toxicity, metabolism

How do we build it?

25 million chemicals from 400 data sources We deal in Molfiles or SDF files – including

coordinates We do rudimentary filtering – valence checking,

charge imbalance – prior to deposition We have our own “business logic” to standardize We use InChI to “aggregate tautomers” to one

record We link out to external sites where possible using

their IDs

Inherited Errors

We have inherited errors from every database… all public compound databases, including ours, have errors

“Incorrect” structures – assertions, timelines etc “Incorrect” names associated with structures Properties Links Publications ENORMOUS CHALLENGE

Compounds and Identifiers

Be careful searching by Name!

Determining the correct structure by name searching is difficult online! Good, not perfect Wikipedia ChEBI/ChEMBL ChemIDPlus ChemSpider

Be VERY careful with MOST databases

Validating structures

Check for “full stereo” and use stereo descriptors especially for checking!

Check for quality of associated data sources Check against reference literature when available

– but it can be wrong Question EVERYTHING!

Online Curation

Online databases generally do NOT allow curation or annotation

If you find errors they stay there! ChemSpider is unique…immediate curation

ChemSpider live demo following this lecture Searching Deposition and Curation ChemSpider SyntheticPages

Thank you

Email: williamsa@rsc.org Twitter: ChemConnectorBlog: www.chemspider.com/blogPersonal Blog: www.chemconnector.comSLIDES: www.slideshare.net/AntonyWilliams