ChemSpider – An Online Database and Registration System Linking the Web

Antony Williams and Valery TkachenkoEBI Chemical Registry Systems Workshop, October 2011

www.chemspider.com

ChemSpider…

>26 million unique molecules from >400 sources .NET, SQL Server and GGA Indigo toolkit Multiple Open Source components – Jmol,

JSpecView, Balloon, OpenBabel, MediaWiki Slices of data are Open but the entire data

collection is not Open Crowdsourced depositions and curations

Uses InChIs for navigating and linking the web

Vancomycin

Vancomycin

Search Molecular SKELETON

Search Full Molecule

Full Skeleton Search: 104 Hits

Full Molecule Search: 4 Hits

ChemSpider…

>26 million unique molecules from >400 sources .NET, SQL Server and GGA Indigo toolkit Multiple Open Source components – Jmol,

JSpecView, Balloon, OpenBabel, MediaWiki Slides of data are Open but the entire data

collection is not Open Crowdsourced depositions and curations

Uses InChIs for navigating and linking the web Uses Names for navigating and linking the web

I want to know about “Vincristine”

If all algorithms work then everything on the page is correct by default except the name-structure relationship!

Vincristine: Identifiers and Properties

Vincristine: Vendors and SourcesLinked by Structure

Vincristine: PatentsLinked by Name

Vincristine: ArticlesLinked by Name

ORIGINAL ChemSpider

“Create a system for linking and navigating databases on the web”

Use the power of InChI, and the proliferation of InChIs in databases, to make connectionsDeveloped on .NET and SQL Server for speed of implementation and existing skill setsSeeded with PubChem database of 10.5M chemicals and expanded using other sources to 20M

How do we build it?

We deal in Molfiles or SDF files – with coordinates

Deposit anything that has an InChI – we support what InChI can handle, good and bad

Standardization based on “InChI standardization”

InChIs aggregate (certain) tautomers

We link out to external sites using their IDs

InChIs – both on ChemSpider

Downsides of InChI

InChI was a moving target (multi versions) but overall worked as planned.

Good for small molecules – but no polymers, issues with inorganics, organometallics, imperfect stereochemistry. ChemSpider is “small molecules”

InChI used as the “deduplicator” – FIRST version of a compound into the database becomes THE structure to deduplicate against…

Side Effects of InChI Usage

SMILES by comparison…

Side Effects of InChI Usage

Standardization IssuesDepiction based on molfile

Downsides of Overall Approach

Meshing data together based on InChIs worked for simple molecules

2D layout errors inherited or limited by algorithm

Complex molecules that are meant to be the same thing were NOT deduplicated. Compounds differing by one stereocenter, named the same, meant to be the same, are not the same

Yohimbine

Originally 15 compounds “called” Yohimbine54 Skeletons for Yohimbine

ChemSpider as an Aggregator

ChemSpider has inherited many errors, and it continues but we are way more careful now with pre-filtering

Cannot deposit chemicals without an InChI Deprecated compounds remain deprecated

Curated name-structure relationships do NOT remove the related structure If Taxol is removed from 20 asserted “incorrect

structures” those compounds remain in the database

Chemistry Databases on the Internet

Some public databases are “trusted” as primary sources

Trust is granted without investigation or understanding of the content

What do we know about some of the online resources?

PHYSPROP Database

The freely downloadable database under the EPI Suite prediction software

Very Basic filters suggest data quality issues

The Stereochemistry challenge.12500 chemicals with “missed” stereo

Searches on ChemSpider

Most searches are text-based: people searching for information about known chemicals

Creating accurate name-structure dictionaries is critical

NIST Webbook

PubChem

NPC Browser http://tripod.nih.gov/npc/

NPC Browser http://tripod.nih.gov/npc/

NPC Browser http://tripod.nih.gov/npc/

Synonyms on PubChem

1,3-DICHLORO-PROPAN-2-ONE

(2R,3R)-Butanediol bis(methanesulfonate)

Ethyl-1-propenyl ether, mixture of cis and trans

PSS-[2-[(Chloromethyl)phenyl]ethyl]-Heptaisobutyl substituted

1-Chlorobenzylethyl-3,5,7,9,11,13,15-heptaisobutylpentacyclo [9.5.1.1(3,9).1(5,15).1(7,13)]octasiloxane

Synonyms on PubChem

Data Proliferation

What is meant by a name?

Choose a Starting Point

“The First 10”

What is getting into Our Databases?

Large aggregators are inheriting junk data

Data HAS proliferated from ChemSpider through PubChem – in process of deprecating and redepositing

A lot of data is for chemicals that will never exist (probably)

Standardization of Patent Data???

Standardization of Patent Data???

WYSIWYG compounds

WYSIWYG compounds

Text Mining Chemical Name Errors

“DPA”

All aggegators suffer dilution!

Structures have timelines

Name-Structure Dictionaries…

Depiction for Humans

Human Depiction versus Algorithms

Human Depiction versus Algorithms

Identifier Dictionaries

Reciprocal curation processes…share curation with each other.

If a database has a compound already then use InChiKeys to match “suggested” validation against the compound.

A series of “added” and “removed” synonyms against InChIKeys for matching.

Proof of Concept Data Curation Sharing

Structure Validation using feed

Look for approved synonyms

Compare feed InChIKey with database InChIKey

If different, flag for inspection

Open PHACTS : partnership between European Community and EFPIA

Freely accessible for knowledge discovery and verification. Data on small molecules Pharmacological profiles Pharmacokinetics ADMET data Biological targets and pathways Proprietary and public data sources.

Adopting Modified FDA Rules

As already used by ChEMBL…

Nitro groups

Salt and Ionic Bonds

Ammonium salts

Parent and Child

Chemical entities reduced to primary component plus relationships salt forms solvates combinations

ChemSpider Standardization

Entire ChemSpider database will be standardized using modified FDA rule set

Original Molfiles will be standardized and all properties (predicted properties, SMILES, InChIs, Names) will all be regenerated

Standardization procedures automatically applied to all future depositions

Project Status

Standardization pipelining process initiated Rule implementation and checking – iterative

work with Open PHACTS pharma members Data model development to support parent-child

relationships

In dialog with the FDA about latest form of recommendations

Conclusions ChemSpider has an important role in quality data

Crowdsourced deposition, validation and curation works but low engagement to date

Standardization of our entire backfile is necessary

Designing the standardization processes with input from pharma and general chemists is necessary

Acknowledgments

The ChemSpider team

Our data providers, depositors, collaborators and curators

Software providers – OpenEye, ChemDoodle, ACD/Labs, GGA Software, Open Source (Jmol, JSpecView, OpenBabel)

Thank you

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