This document summarizes a presentation about accessing chemical data using the ChEBI database. It introduces ChEBI as a manually annotated database and ontology of small chemical entities. It covers searching and browsing ChEBI, understanding the ChEBI ontology structure, and methods for programmatic access including downloads of the ChEBI data in different file formats and via a web service API.

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

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

3. Introduction to ChEBI Block 1

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

5. 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

6. Small molecules participate in all the processes of life

7. 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

8. 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

9. 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

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

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

12. 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

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

14. 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

15. 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

16. 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 , …

17. 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

18. 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 – Chemical Entities of Biological Interest 25.02.10

19. ChEBI home page ChEBI – Chemical Entities of Biological Interest 25.02.10

20. 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 – Chemical Entities of Biological Interest 25.02.10

21. 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 – Chemical Entities of Biological Interest 25.02.10

22. ChEBI entry view ChEBI – Chemical Entities of Biological Interest 25.02.10

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

24. Chemical Structures Chemical structure may be interactively explored using MarvinView applet Available in formats Image Molfile InChI and InChIKey SMILES ChEBI – Chemical Entities of Biological Interest 25.02.10

25. Molfile format ChEBI – Chemical Entities of Biological Interest 25.02.10

26. Time for Exercises

27. Searching and browsing ChEBI Block 2

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

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

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

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

32. Fingerprints Chemical substructure searching is computationally expensive… ChEBI – Chemical Entities of Biological Interest 25.02.10

33. 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…

34. 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

35. 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

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

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

38. Time for Exercises

39. Understanding the ChEBI ontology Block 3

40. 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… ChEBI – Chemical Entities of Biological Interest 25.02.10 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

41. 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

42. Molecular structure ontology ChEBI – Chemical Entities of Biological Interest 25.02.10

43. Role ontology ChEBI – Chemical Entities of Biological Interest 25.02.10

44. ChEBI ontology relationships Generic ontology relationships Chemistry-specific relationships ChEBI – Chemical Entities of Biological Interest 25.02.10

45. Viewing ChEBI ontology ChEBI – Chemical Entities of Biological Interest 25.02.10

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

47. 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/

48. 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 ChEBI – Chemical Entities of Biological Interest 25.02.10

49. 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

50. Time for Exercises

51. Download and programmatic access Block 4

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

53. 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

54. 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

55. 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)

56. 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 ChEBI – Chemical Entities of Biological Interest 25.02.10

57. 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

58. SDF File Lite format Chemistry software compliant format Why use this 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 $$$$

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

60. Flat-file tab and comma delimited ChEBI – Chemical Entities of Biological Interest 25.02.10 Why use this format? 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

61. Table dumps Similar structure to the flat-file tab delimited files Why use this format? 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 ChEBI – Chemical Entities of Biological Interest 25.02.10

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

63. 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 . ChEBI – Chemical Entities of Biological Interest 25.02.10

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

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

66. Methods and parameters (2) ChEBI – Chemical Entities of Biological Interest 25.02.10

67. Methods and parameters (3) ChEBI – Chemical Entities of Biological Interest 25.02.10

68. Time for Exercises

69. 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 ChEBI – Chemical Entities of Biological Interest 25.02.10

70. 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. ChEBI – Chemical Entities of Biological Interest 25.02.10

71. Thank you