The Importance of the InChI Identifier as a Foundation Technology for eScience Platforms at RSC

Antony Williams

Bio-IT,

Boston, April 27th 2014

Without the InChI…

• ChemSpider is unlikely to have been built

• It would not have grown into one of the domains primary online chemistry resources

• The Royal Society of Chemistry would not have it as an online database, would not have a large cheminformatics team and would not be involved in a number of large scale funded projects around chemistry data

• ~30 million chemicals and growing

• Data sourced from >500 different sources

• Crowd sourced curation and annotation

• Ongoing deposition of data from our journals and our collaborators

• Structure centric hub for web-searching

• …and a really big dictionary!!!

ChemSpider

ChemSpider

Experimental/Predicted Properties

Literature references

Patents references

So what is Yohimbine?

Of course it is out there…

Drugbox: 3001/5080 with InChIs Chembox:5436/7690 with InChIs

Tell me more…

• Where can I find the molfile for Yohimbine?• Papers/Patents about Yohimbine?• What are the side effects of Yohimbine?• Where can I order Yohimbine?• What are the physicochemical properties?• Metabolic pathways?• Different synonyms of Yohimbine?• Synthesis of Yohimbine?• Side effects of Yohimbine?• Etc….

Quantity!

Yohimbine on ChemSpider

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 on ChemSpider..Quality?

So where can we travel???

So where can we travel???

InChI String Search via GoogleGive me InChIKeys…

And where can we travel???

ChemSpider

BRENDA

Wikipedia

ChEMBL

ChEBI

DrugBank

Aggregator

Enzymes

Encyclopedia

Pharmacology

Curated Chemicals

Drug-Drug Target

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

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

Standardize

Use the SRS as a guidance document for standardizationAdjust as necessary to our needs

Nitro groups

Salt and Ionic Bonds

Ammonium salts

CVSP

NPC Browser Set

Checking include InChI

• Many SDF files contain InChIs and SMILES – comparing the structure contained within the file with the associated InChI is useful – turned up a number of errors in checking online databases

So, I’m writing an article…

With these…I will lose data

But linking with InChI …

Structure Searching the Web

Data in Publications

• This is not new, you know the story…• So much data of value is contained within a

publication and delivered in a PDF form• PDF files, and unclear licensing/copyright, limit

access to data so I can rework, reuse, repurpose, text mine etc.

• “I specialize in XXXX. I want a database of YYYY extracted from publications and made available, for free, with the capabilities I need, and the publishers should just do it”

“Data enable” publications?

• We would LOVE to bring data out of our archive• What could we do?

• Find chemical names and generate structures• Find chemical images and generate structures• Find reactions – and make a database!• Find data (MP, BP, LogP) and host. Build

models!• Find figures and database them• Find spectra (and link to structures)• Validate the data algorithmically

RSC Archive – since 1841

Text Mining

The N-(β-hydroxyethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)urea prepared in Example 6 , thionyl chloride ( 5 ml ) and benzene ( 50 ml ) were charged into a glass reaction vessel equipped with a mechanical stirrer , thermometer and reflux condenser .

The reaction mixture was heated at reflux with stirring , for a period of about one-half hour .

After this time the benzene and unreacted thionyl chloride were stripped from the reaction mixture under reduced pressure to yield the desired product N-(β-chloroethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiaidazol-5-yl)urea as a solid residue

Text Mining

The N-(β-hydroxyethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)urea prepared in Example 6 , thionyl chloride ( 5 ml ) and benzene ( 50 ml ) were charged into a glass reaction vessel equipped with a mechanical stirrer , thermometer and reflux condenser .

The reaction mixture was heated at reflux with stirring , for a period of about one-half hour .

After this time the benzene and unreacted thionyl chloride were stripped from the reaction mixture under reduced pressure to yield the desired product N-(β-chloroethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiaidazol-5-yl)urea as a solid residue

But names = structures

• Systematic names can be generated FROM chemical structures algorithmically

But names = structures

• …and structures from systematic names

But what of trivial names?

• What about trivial names, trade names, CAS numbers, multilingual names etc.?

Searching that lipid in patents

Aspirin on ChemSpider

Work in Progress

Work in Progress

Work in Progress

Work in Progress

But Context Gives Reactions

The N-(β-hydroxyethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)urea prepared in Example 6 , thionyl chloride ( 5 ml ) and benzene ( 50 ml ) were charged into a glass reaction vessel equipped with a mechanical stirrer , thermometer and reflux condenser .

The reaction mixture was heated at reflux with stirring , for a period of about one-half hour .

After this time the benzene and unreacted thionyl chloride were stripped from the reaction mixture under reduced pressure to yield the desired product N-(β-chloroethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiaidazol-5-yl)urea as a solid residue

ChemSpider Reactions

ChemSpider as a Foundation

• >30 million chemicals (and growing)

• ChemSpider is free to access for everyone – and the API means people program against it

• What projects can we benefit?

Support grant-based services• Multiple European consortium-based grants

• PharmaSea (FP7 funded)• Open PHACTS (IMI funded)

• UK National Chemical Database Service (http://cds.rsc.org) – developing data repository for lab data, integrate Electronic Lab Notebooks

• Open Drug Discovery projects

PharmaSea

• 3-year Innovative Medicines Initiative project

• Integrating chemistry and biology data using semantic web technologies

• Open code, open data, open standards

• Academics, Pharmas, Publishers…

• To put medicines in the pipeline…

Open PHACTS

All Databases We Generate…

• All databases and systems we build now include generated InChIs

• InChIs are facilitating discoverability via searching on Google (see Chris’ talk) but also for querying and linking

But we are still VERY LIMITED

• RSC deals with way more than organics, inorganics, organometallics – we are building a data repository to include materials, polymers, ambiguous materials etc.

• There are many plans for InChI moving forward – Markush, polymers, organometallics etc

The great promise should be obvious

• InChIs are here to stay• They will evolve, they will encompass, we

will adopt and adapt• Public and private databases will federate &

build a linked environment of validated data!• Data validation and standardization is

needed• Open Data will continue to proliferate• InChIs are in the “Semantic Web” already

If InChI never existed …

• ChemSpider would never have been built

• Database linking would suffer dramatically

• The web would not be “structure searchable”

• Cheminformatics tools would likely not be linking to public domain databases in the same way

Thank youEmail: williamsa@rsc.orgORCID: 0000-0002-2668-4821 Twitter: @ChemConnectorPersonal Blog: www.chemconnector.com SLIDES: www.slideshare.net/AntonyWilliams