Accessing small molecule data using ChEBI

Accessing small molecule data using ChEBI Janna Hastings, Duncan Hull and Nico Adams Programmatic Access to Biological Databases (Perl) 22-26 February 2010 @ EBI

Overview
Introduction to ChEBI
Searching and browsing
Understanding the ontology
Downloads and programmatic access
ChEBI – Chemical Entities of Biological Interest 25.02.10

Introduction to ChEBI Block 1

Small Molecules within Bioinformatics Literature Nucleotide sequences Genomes Expressions Protein sequences Protein domains, families 3D structures Enzymes Small molecules Pathways Systems

Literature Nucleotide sequences Genomes Expressions Protein sequences Protein domains, families 3D structures Enzymes Small molecules Pathways Systems Small Molecules within Bioinformatics Small molecules Small molecules Small molecules Small molecules Small molecules

Small molecules participate in all the processes of life

Signaling γ-aminobutyric acid
GABA: chief inhibitory neurotransmitter in the mammalian central nervous system.
In humans, also regulates muscle tone.
synthesized by neurons
found mostly as a zwitterion , that is, with the carboxyl group deprotonated and the amino group protonated (ChEBI:16865)
conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations
GABA deficiency linked to
anxiety disorder, depression, alcoholism
multiple sclerosis, action tremors, tardive dyskinesia

Metabolism
Adenosine 5’-triphosphate (ATP): the
"molecular unit of currency" of intracellular
energy transfer . (ChEBI:15422)
generated in the cell by energy-consuming processes, broken down by energy-releasing processes
proteins that bind ATP do so in a characteristic protein fold known as the Rossmann fold , which is a general nucleotide-binding structural domain that can also bind the cofactor NAD
Adenosine 5'-triphosphate

Enzymes
Enzyme inhibitors are molecules that bind to enzymes and decrease their activity.
Many drugs are enzyme inhibitors. They are also used as herbicides and pesticides.
Enzyme activators bind to enzymes and increase their enzymatic activity.
Enzyme activators are often involved in the allosteric regulation of enzymes in the control of metabolism.
clavulanic acid (ChEBI:48947) acts as a suicide inhibitor of bacterial β-lactamase enzymes

Pathways http://www.genome.jp/kegg-bin/highlight_pathway?scale=1.0&map=map00231&keyword=tryptophan

Systems biology
BioModels: quantitative models of biochemical and cellular systems
tryptophan
D-enantiomer: sweet L-enantiomer: bitter

Drug design
Ligand-based : relies on knowledge of other molecules that bind to the biological target of interest.
Structure-based : relies on knowledge of the 3D structure of the biological target.
A lead has
evidence that modulation of the target will have therapeutic value : e.g. disease linkage studies showing associations between mutations in the biological target and certain disease states.
evidence that the target is druggable , i.e. capable of binding to a small molecule and that its activity can be modulated by the small molecule.
Target is cloned and expressed, then libraries of potential drug compounds are screened using screening assays

Drug types 2003 - 2009 'Small molecules' in various shades of blue (http://chembl.blogspot.com/)

Getting the chemistry right
Thalidomide a non-barbiturate hypnotic
Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action.
Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: one enantiomer is effective against morning sickness , and the other is teratogenic .
Enantiomers are interconverted in vivo . That is, if a human is given D-thalidomide or L-thalidomide, both isomers can be found in the serum. Hence, administering only one enantiomer does not prevent the teratogenic effect in humans.
http://www.drugbank.ca/drugs/DB01041

Small molecule data sources Deposition-driven publicly available compound repository, containing more than 25 million unique structures. http://pubchem.ncbi.nlm.nih.gov/ http://www.chemspider.com/ Automatic aggregation of publicly available chemistry data with crowdsourced annotation. http://www.ebi.ac.uk/chebi/ Manually annotated database and ontology

Small molecule annotations
Often appear as free text in biological databases, in which they are not the core data
Are frequently referred to by common names which may be chemically ambiguous
eg. adrenaline
= (S)-adrenaline ? (R)-adrenaline ?
May be referred to by several different names
paracetamol, acetaminophen, 4-acetamidophenol, N -(4-hydroxyphenyl)acetamide , …

Chemicals - ChEBI Visualisation caffeine 1,3,7-trimethylxanthine methyltheobromine Nomenclature Formula: C8H10N4O2 Charge: 0 Mass: 194.19 Chemical data metabolite CNS stimulant trimethylxanthines Ontology MSDchem: CFF KEGG DRUG: D00528 Database Xrefs Chemical Informatics InChI=1/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3 SMILES CN1C(=O)N(C)c2ncn(C)c2C1=O

What is ChEBI?
Ch emical E ntities of B iological I nterest
Freely available
Focused on ‘small’ chemical entities (no proteins or nucleic acids)
Illustrated dictionary of chemical nomenclature
High quality, manually annotated
Provides chemical ontology
Access ChEBI at http://www.ebi.ac.uk/chebi/

ChEBI home page ChEBI – Chemical Entities of Biological Interest 25.02.10

How is ChEBI maintained?
Automatic loading of preliminary data
Automatic loading of 2 star annotated data (ChEMBL and others)
Manual annotation
User requests via Submission Tool
Public release: First Wednesday of every month.

ChEBI entries contain
A unique , unambiguous, recommended ChEBI name and an associated stable unique identifier
An illustration where appropriate (compounds and groups, but generally not classes)
A definition where appropriate (mostly classes)
A collection of synonyms , including the IUPAC recommended name for the entity where appropriate
A collection of cross-references to other databases
Links to the ChEBI ontology

ChEBI entry view ChEBI – Chemical Entities of Biological Interest 25.02.10

Automatic Cross-references ChEBI – Chemical Entities of Biological Interest 25.02.10

Chemical Structures
Chemical structure may be interactively explored using MarvinView applet
Available in formats
Image
Molfile
InChI and InChIKey
SMILES

Molfile format ChEBI – Chemical Entities of Biological Interest 25.02.10

Time for Exercises

Searching and browsing ChEBI Block 2

Simple text search
Simple text search ChEBI – Chemical Entities of Biological Interest 25.02.10 Wildcard: * Enter any text

Advanced text search ChEBI – Chemical Entities of Biological Interest 25.02.10 Narrow to category AND, OR and BUT NOT

Structure search ChEBI – Chemical Entities of Biological Interest 25.02.10 Search options Structure drawing tools

Search Results ChEBI – Chemical Entities of Biological Interest 25.02.10 Click to go to entry page Hover-over for search menu

Fingerprints
Chemical substructure searching is computationally expensive…

Fingerprints [2]
… so heuristics must be used to decrease the number of search candidates
ChEBI – Chemical Entities of Biological Interest 25.02.10 C8H9NO2
Fingerprints are a generalized, abstract encoding of structural features which can be used as an effective screening device
cannot be a substructure of an entity which does not have at least 8 carbon atoms, 9 hydrogen atoms…

Fingerprints [3]
Encoding of structural patterns
ChEBI – Chemical Entities of Biological Interest 25.02.10 water (HOH) 0-bond paths H O H 1-bond paths HO OH 2-bond paths HOH
Hashed to create bit strings, which are added together to give final fingerprint
Pattern Hashed bitmap H 0000010000 O 0010000000 HO 1010000000 OH 0000100010 HOH 0000000101 Result: 1010110111

Types of structure search
Identity – based on InChI
Substructure – uses fingerprints to narrow search range, then performs full substructure search algorithm
Similarity – based on Tanimoto coefficient calculated between the fingerprints
ChEBI – Chemical Entities of Biological Interest 25.02.10 InChI=1/H2O/h1H2 1010110111 0010110010 10 1 0 11 01 1 1 00 1 0 11 00 1 0 Tanimoto(a,b) = c / (a+b-c) = 4 / ( 4 + 7 - 4 ) = 0.57 a b

Browse via Periodic Table ChEBI – Chemical Entities of Biological Interest 25.02.10 Molecular entities / Elements

Navigate via links in ontology ChEBI – Chemical Entities of Biological Interest 25.02.10 Click to follow links

Time for Exercises

Understanding the ChEBI ontology Block 3

Annotation of bioinformatics data
Essential for capturing understanding and knowledge associated with core data
Often captured in free text, which is easier to read and better for conveying understanding to a human audience, but…
Difficult for computers to parse
Quality varies from database to database
Terminology used varies from annotator to annotator
Towards annotation using standard vocabularies : ontologies within bioinformatics

The ChEBI ontology
Organised into three sub-ontologies, namely
Molecular structure ontology
Subatomic particle ontology
Role ontology
ChEBI – Chemical Entities of Biological Interest 25.02.10 ( R ) -adrenaline

Molecular structure ontology ChEBI – Chemical Entities of Biological Interest 25.02.10

Role ontology ChEBI – Chemical Entities of Biological Interest 25.02.10

ChEBI ontology relationships
Generic ontology relationships
Chemistry-specific relationships

Viewing ChEBI ontology ChEBI – Chemical Entities of Biological Interest 25.02.10

Viewing ChEBI ontology [2] ChEBI – Chemical Entities of Biological Interest 25.02.10 Tree view

Browsing ChEBI ontology (OLS) ChEBI – Chemical Entities of Biological Interest 25.02.10 Browse the ontology Ontology Lookup Service (OLS): http://www.ebi.ac.uk/ontology-lookup/

Ontology Lookup Service
Provides a centralised query interface for ontology and controlled vocabulary lookup
Can integrate any ontology available in OBO format
At last release, 58 ontologies integrated, including
GO
ChEBI
Molecular interaction (PSI MI)
Pathway ontology (PW)
Human disease (DOID)
and many more…
Provides a search and a browse facility, as well as displaying a graph of terms and relationships

OBO Foundry “ The OBO Foundry is a collaborative experiment involving developers of science-based ontologies who are establishing a set of principles for ontology development with the goal of creating a suite of orthogonal interoperable reference ontologies in the biomedical domain.” ChEBI – Chemical Entities of Biological Interest 25.02.10

Time for Exercises

Download and programmatic access Block 4

ChEBI domain model ChEBI – Chemical Entities of Biological Interest 25.02.10 Self-referencing - merging

Compound IDs and Merging
Compound accessions are maintained after merging, but…
ChEBI – Chemical Entities of Biological Interest 25.02.10 only the main accession of a merged group is displayed Navigated accession: CHEBI:5585 Main accession: CHEBI:15377

Compound IDs and Merging [2] ChEBI – Chemical Entities of Biological Interest 25.02.10 Additional acc Parent ID This compound ID = additional acc ID STATUS CHEBI_ACCN SOURCE PARENT_ID NAME DEFINITION 15377 C CHEBI:15377 ChEBI null water null 5585 C CHEBI:5585 KEGG 15377 null null ID COMPOUND ACCN_NUMBER TYPE STATUS SOURCE URL_ABBR 16213 5585 C00001 KEGG accn C KEGG KEGG 17314 5585 7732-18-5 CAS Registry C KEGG null

Downloading ChEBI flavours ChEBI – Chemical Entities of Biological Interest 25.02.10
All downloads come in two flavours
3 star only entries (manually annotated ChEBI entries)
2 and 3 star entries (manually annotated ChEBI, ChEMBL and user submissions)

Downloading ChEBI
OBO file
Use on OBO-edit
SDF File
Chemistry software compliant such as Bioclipse
Flat file, tab delimited
Import all the data into Excel
Parse it into your own database structure
Oracle binary dumps
Import into an oracle database
Generic SQL insert statements
Import into MySQL or postgresql database

OBO File Format
File format defined specifically for capturing biological ontologies
Why use this format?
Use it if you are primarily interested in the ontology.
Don’t use it if you are interested in chemical structural information.
What can you do with it?
Can parse it directly using parsers such as OBO-Edit
Can upload and browse the ontology using OBO-Edit
ChEBI – Chemical Entities of Biological Interest 25.02.10 General header information Synonym types used in terms Root terms Relationships to other terms

SDF File Lite format
Chemistry software compliant format
Use it to obtain the ChEBI entries with their chemical structural information.
Don’t use it for the ontology.
What can I do with this format?
Parse it using existing software libraries such as CDK.
Open it in standalone tools such as Bioclipse
Copy and paste individual structures into JChemPaint
ChEBI – Chemical Entities of Biological Interest 25.02.10 Entries separated by $$$$

SDF File complete format ChEBI – Chemical Entities of Biological Interest 25.02.10 Entries separated by $$$$

Flat-file tab and comma delimited ChEBI – Chemical Entities of Biological Interest 25.02.10
Use it to obtain the entire ChEBI database structure.
What can I do with this format?
Open it using Excel
Import it into a relevant database such as Oracle

Table dumps
Similar structure to the flat-file tab delimited files
Use it to obtain the entire ChEBI database structure.
Oracle binary dumps
Import into an oracle database
Generic SQL insert statements
Import into MySQL or postgresql database

Web services
Allow users to create their own applications to query data
ChEBI – Chemical Entities of Biological Interest 25.02.10 User application

The ChEBI web service
Programmatic access to a ChEBI entry
SOAP based Java implementation
Clients currently available in Java and perl
Methods
getLiteEntity
getCompleteEntity and getCompleteEntityByList
getOntologyParents
getOntologyChildren and getAllOntologyChildrenInPath
getStructureSearch
Documented at http://www.ebi.ac.uk/chebi/webServices.do .

Web service client object model ChEBI – Chemical Entities of Biological Interest 25.02.10 getLiteEntity getCompleteEntity getOntology (Parents and Children)

Methods and parameters (1) ChEBI – Chemical Entities of Biological Interest 25.02.10

Time for Exercises

For more information
ftp://ftp.ebi.ac.uk/pub/software/webservices/Perl/WSChebiSOAPLite-2.0.zip
Email : [email_address]
SourceForge: https://sourceforge.net/projects/chebi/
User Manual: http://www.ebi.ac.uk/chebi/userManualForward.do
RSS Feed

Acknowledgements
The ChEBI team
Nico Adams Paula de Matos
Adriano Dekker Marcus Ennis
Janna Hastings Duncan Hull
Zara Josephs Steve Turner
Christoph Steinbeck
Everyone @ the EBI and elsewhere who uses or contributes to ChEBI
ChEBI is funded by the European Commission under SLING, grant agreement number 226073 (Integrating Activity) within Research Infrastructures of the FP7 Capacities Specific Programme; and by the BBSRC, grant agreement number BB/G022747/1 within the "Bioinformatics and biological resources" fund.

Thank you

Accessing small molecule data using ChEBI

by Duncan Hull on Feb 25, 2010

Accessibility

Tags

Upload Details

Usage Rights

1 Embed 9

Statistics

Accessing small molecule data using ChEBI — Presentation Transcript