Accessing small molecule data using ChEBI

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Presentation on Chemical Entities of Biological Interest (ChEBI) for the Programmatic Access to Biological Databases (Perl) course
22-26 February 2010 @ EBI

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  • Databases - ChEBI
  • Time taken to perform a full substructure search increases exponentially with the number of atoms. So, running the full search against the entire database is an intractable problem.
  • Molecular formula provides a crude heuristic for narrowing the number of search candidates in a substructure search. Fingerprints are a much more powerful device.
  • An algorithm generates patterns for each atom, each bonded group of two atoms, three… up to 8 bonds long. Each pattern is then hashed into a bit string, and the hashed results are all then added together using the logical OR relationship to create the final fingerprint.
  • Identity search is subject to the limitations of InChI uniqueness, however, in general, identity search will find exactly the structure you have entered, if it exists in the database. For substructure searching, the fingerprint is used to narrow the range of search candidates from the database based on the fingerprint property that all bits set in the substructure fingerprint, are also set in the structure fingerprint. For similarity, the Tanimoto coefficient is calculated from the fingerprints based on T = c/(a + b – c).
  • When trying to retrieve the compound accession from a data item such as a database accession or compound name, the relevant entry in the Compounds table must also be retrieved and the parent_id field examined. If the parent_id is not empty, then it links to the compound containing the primary identifier for this merged group of entities. There are more ID’s than just one, for a given compound,
  • Accessing small molecule data using ChEBI

    1. 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. 2. Overview <ul><li>Introduction to ChEBI </li></ul><ul><li>Searching and browsing </li></ul><ul><li>Understanding the ontology </li></ul><ul><li>Downloads and programmatic access </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    3. 3. Introduction to ChEBI Block 1
    4. 4. Small Molecules within Bioinformatics Literature Nucleotide sequences Genomes Expressions Protein sequences Protein domains, families 3D structures Enzymes Small molecules Pathways Systems
    5. 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. 6. Small molecules participate in all the processes of life
    7. 7. Signaling γ-aminobutyric acid <ul><li>GABA: chief inhibitory neurotransmitter in the mammalian central nervous system. </li></ul><ul><li>In humans, also regulates muscle tone. </li></ul><ul><li>synthesized by neurons </li></ul><ul><li>found mostly as a zwitterion , that is, with the carboxyl group deprotonated and the amino group protonated (ChEBI:16865) </li></ul><ul><li>conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations </li></ul><ul><li>GABA deficiency linked to </li></ul><ul><ul><li>anxiety disorder, depression, alcoholism </li></ul></ul><ul><ul><li>multiple sclerosis, action tremors, tardive dyskinesia </li></ul></ul>
    8. 8. Metabolism <ul><li>Adenosine 5’-triphosphate (ATP): the </li></ul><ul><li>&quot;molecular unit of currency&quot; of intracellular </li></ul><ul><li>energy transfer . (ChEBI:15422) </li></ul><ul><li>generated in the cell by energy-consuming processes, broken down by energy-releasing processes </li></ul><ul><li>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 </li></ul>Adenosine 5'-triphosphate
    9. 9. Enzymes <ul><li>Enzyme inhibitors are molecules that bind to enzymes and decrease their activity. </li></ul><ul><li>Many drugs are enzyme inhibitors. They are also used as herbicides and pesticides. </li></ul><ul><li>Enzyme activators bind to enzymes and increase their enzymatic activity. </li></ul><ul><li>Enzyme activators are often involved in the allosteric regulation of enzymes in the control of metabolism. </li></ul>clavulanic acid (ChEBI:48947) acts as a suicide inhibitor of bacterial β-lactamase enzymes
    10. 10. Pathways http://www.genome.jp/kegg-bin/highlight_pathway?scale=1.0&map=map00231&keyword=tryptophan
    11. 11. Systems biology <ul><li>BioModels: quantitative models of biochemical and cellular systems </li></ul><ul><li>tryptophan </li></ul>D-enantiomer: sweet L-enantiomer: bitter
    12. 12. Drug design <ul><li>Ligand-based : relies on knowledge of other molecules that bind to the biological target of interest. </li></ul><ul><li>Structure-based : relies on knowledge of the 3D structure of the biological target. </li></ul><ul><li>A lead has </li></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><li>Target is cloned and expressed, then libraries of potential drug compounds are screened using screening assays </li></ul>
    13. 13. Drug types 2003 - 2009 'Small molecules' in various shades of blue (http://chembl.blogspot.com/)
    14. 14. Getting the chemistry right <ul><li>Thalidomide a non-barbiturate hypnotic </li></ul><ul><li>Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. </li></ul><ul><li>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 . </li></ul><ul><li>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. </li></ul>http://www.drugbank.ca/drugs/DB01041
    15. 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. 16. Small molecule annotations <ul><li>Often appear as free text in biological databases, in which they are not the core data </li></ul><ul><li>Are frequently referred to by common names which may be chemically ambiguous </li></ul><ul><ul><li>eg. adrenaline </li></ul></ul><ul><ul><li>= (S)-adrenaline ? (R)-adrenaline ? </li></ul></ul><ul><li>May be referred to by several different names </li></ul><ul><ul><li>paracetamol, acetaminophen, 4-acetamidophenol, N -(4-hydroxyphenyl)acetamide , … </li></ul></ul>
    17. 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. 18. What is ChEBI? <ul><li>Ch emical E ntities of B iological I nterest </li></ul><ul><li>Freely available </li></ul><ul><li>Focused on ‘small’ chemical entities (no proteins or nucleic acids) </li></ul><ul><li>Illustrated dictionary of chemical nomenclature </li></ul><ul><li>High quality, manually annotated </li></ul><ul><li>Provides chemical ontology </li></ul><ul><li>Access ChEBI at http://www.ebi.ac.uk/chebi/ </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    19. 19. ChEBI home page ChEBI – Chemical Entities of Biological Interest 25.02.10
    20. 20. How is ChEBI maintained? <ul><li>Automatic loading of preliminary data </li></ul><ul><li>Automatic loading of 2 star annotated data (ChEMBL and others) </li></ul><ul><li>Manual annotation </li></ul><ul><li>User requests via Submission Tool </li></ul><ul><li>Public release: First Wednesday of every month. </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    21. 21. ChEBI entries contain <ul><li>A unique , unambiguous, recommended ChEBI name and an associated stable unique identifier </li></ul><ul><li>An illustration where appropriate (compounds and groups, but generally not classes) </li></ul><ul><li>A definition where appropriate (mostly classes) </li></ul><ul><li>A collection of synonyms , including the IUPAC recommended name for the entity where appropriate </li></ul><ul><li>A collection of cross-references to other databases </li></ul><ul><li>Links to the ChEBI ontology </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    22. 22. ChEBI entry view ChEBI – Chemical Entities of Biological Interest 25.02.10
    23. 23. Automatic Cross-references ChEBI – Chemical Entities of Biological Interest 25.02.10
    24. 24. Chemical Structures <ul><li>Chemical structure may be interactively explored using MarvinView applet </li></ul><ul><li>Available in formats </li></ul><ul><ul><li>Image </li></ul></ul><ul><ul><li>Molfile </li></ul></ul><ul><ul><li>InChI and InChIKey </li></ul></ul><ul><ul><li>SMILES </li></ul></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    25. 25. Molfile format ChEBI – Chemical Entities of Biological Interest 25.02.10
    26. 26. Time for Exercises
    27. 27. Searching and browsing ChEBI Block 2
    28. 28. <ul><li>Simple text search </li></ul>Simple text search ChEBI – Chemical Entities of Biological Interest 25.02.10 Wildcard: * Enter any text
    29. 29. Advanced text search ChEBI – Chemical Entities of Biological Interest 25.02.10 Narrow to category AND, OR and BUT NOT
    30. 30. Structure search ChEBI – Chemical Entities of Biological Interest 25.02.10 Search options Structure drawing tools
    31. 31. Search Results ChEBI – Chemical Entities of Biological Interest 25.02.10 Click to go to entry page Hover-over for search menu
    32. 32. Fingerprints <ul><li>Chemical substructure searching is computationally expensive… </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    33. 33. Fingerprints [2] <ul><li>… so heuristics must be used to decrease the number of search candidates </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10 C8H9NO2 <ul><li>Fingerprints are a generalized, abstract encoding of structural features which can be used as an effective screening device </li></ul>cannot be a substructure of an entity which does not have at least 8 carbon atoms, 9 hydrogen atoms…
    34. 34. Fingerprints [3] <ul><li>Encoding of structural patterns </li></ul>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 <ul><li>Hashed to create bit strings, which are added together to give final fingerprint </li></ul>Pattern Hashed bitmap H 0000010000 O 0010000000 HO 1010000000 OH 0000100010 HOH 0000000101 Result: 1010110111
    35. 35. Types of structure search <ul><li>Identity – based on InChI </li></ul><ul><li>Substructure – uses fingerprints to narrow search range, then performs full substructure search algorithm </li></ul><ul><li>Similarity – based on Tanimoto coefficient calculated between the fingerprints </li></ul>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. 36. Browse via Periodic Table ChEBI – Chemical Entities of Biological Interest 25.02.10 Molecular entities / Elements
    37. 37. Navigate via links in ontology ChEBI – Chemical Entities of Biological Interest 25.02.10 Click to follow links
    38. 38. Time for Exercises
    39. 39. Understanding the ChEBI ontology Block 3
    40. 40. Annotation of bioinformatics data <ul><li>Essential for capturing understanding and knowledge associated with core data </li></ul><ul><li>Often captured in free text, which is easier to read and better for conveying understanding to a human audience, but… </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10 <ul><li>Difficult for computers to parse </li></ul><ul><li>Quality varies from database to database </li></ul><ul><li>Terminology used varies from annotator to annotator </li></ul><ul><li>Towards annotation using standard vocabularies : ontologies within bioinformatics </li></ul>
    41. 41. The ChEBI ontology <ul><li>Organised into three sub-ontologies, namely </li></ul><ul><ul><ul><li>Molecular structure ontology </li></ul></ul></ul><ul><ul><ul><li>Subatomic particle ontology </li></ul></ul></ul><ul><ul><ul><li>Role ontology </li></ul></ul></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10 ( R ) -adrenaline
    42. 42. Molecular structure ontology ChEBI – Chemical Entities of Biological Interest 25.02.10
    43. 43. Role ontology ChEBI – Chemical Entities of Biological Interest 25.02.10
    44. 44. ChEBI ontology relationships <ul><li>Generic ontology relationships </li></ul><ul><li>Chemistry-specific relationships </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    45. 45. Viewing ChEBI ontology ChEBI – Chemical Entities of Biological Interest 25.02.10
    46. 46. Viewing ChEBI ontology [2] ChEBI – Chemical Entities of Biological Interest 25.02.10 Tree view
    47. 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. 48. Ontology Lookup Service <ul><li>Provides a centralised query interface for ontology and controlled vocabulary lookup </li></ul><ul><li>Can integrate any ontology available in OBO format </li></ul><ul><li>At last release, 58 ontologies integrated, including </li></ul><ul><ul><li>GO </li></ul></ul><ul><ul><li>ChEBI </li></ul></ul><ul><ul><li>Molecular interaction (PSI MI) </li></ul></ul><ul><ul><li>Pathway ontology (PW) </li></ul></ul><ul><ul><li>Human disease (DOID) </li></ul></ul><ul><ul><li>and many more… </li></ul></ul><ul><li>Provides a search and a browse facility, as well as displaying a graph of terms and relationships </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    49. 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. 50. Time for Exercises
    51. 51. Download and programmatic access Block 4
    52. 52. ChEBI domain model ChEBI – Chemical Entities of Biological Interest 25.02.10 Self-referencing - merging
    53. 53. Compound IDs and Merging <ul><li>Compound accessions are maintained after merging, but… </li></ul>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. 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. 55. Downloading ChEBI flavours ChEBI – Chemical Entities of Biological Interest 25.02.10 <ul><li>All downloads come in two flavours </li></ul><ul><ul><li>3 star only entries (manually annotated ChEBI entries) </li></ul></ul><ul><ul><li>2 and 3 star entries (manually annotated ChEBI, ChEMBL and user submissions) </li></ul></ul>
    56. 56. Downloading ChEBI <ul><li>OBO file </li></ul><ul><ul><li>Use on OBO-edit </li></ul></ul><ul><li>SDF File </li></ul><ul><ul><li>Chemistry software compliant such as Bioclipse </li></ul></ul><ul><li>Flat file, tab delimited </li></ul><ul><ul><li>Import all the data into Excel </li></ul></ul><ul><ul><li>Parse it into your own database structure </li></ul></ul><ul><li>Oracle binary dumps </li></ul><ul><ul><li>Import into an oracle database </li></ul></ul><ul><li>Generic SQL insert statements </li></ul><ul><ul><li>Import into MySQL or postgresql database </li></ul></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    57. 57. OBO File Format <ul><li>File format defined specifically for capturing biological ontologies </li></ul><ul><li>Why use this format? </li></ul><ul><ul><li>Use it if you are primarily interested in the ontology. </li></ul></ul><ul><ul><li>Don’t use it if you are interested in chemical structural information. </li></ul></ul><ul><li>What can you do with it? </li></ul><ul><ul><li>Can parse it directly using parsers such as OBO-Edit </li></ul></ul><ul><ul><li>Can upload and browse the ontology using OBO-Edit </li></ul></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10 General header information Synonym types used in terms Root terms Relationships to other terms
    58. 58. SDF File Lite format <ul><li>Chemistry software compliant format </li></ul><ul><li>Why use this format? </li></ul><ul><ul><li>Use it to obtain the ChEBI entries with their chemical structural information. </li></ul></ul><ul><ul><li>Don’t use it for the ontology. </li></ul></ul><ul><li>What can I do with this format? </li></ul><ul><ul><li>Parse it using existing software libraries such as CDK. </li></ul></ul><ul><ul><li>Open it in standalone tools such as Bioclipse </li></ul></ul><ul><ul><li>Copy and paste individual structures into JChemPaint </li></ul></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10 Entries separated by $$$$
    59. 59. SDF File complete format ChEBI – Chemical Entities of Biological Interest 25.02.10 Entries separated by $$$$
    60. 60. Flat-file tab and comma delimited ChEBI – Chemical Entities of Biological Interest 25.02.10 <ul><li>Why use this format? </li></ul><ul><ul><li>Use it to obtain the entire ChEBI database structure. </li></ul></ul><ul><li>What can I do with this format? </li></ul><ul><ul><li>Open it using Excel </li></ul></ul><ul><ul><li>Import it into a relevant database such as Oracle </li></ul></ul>
    61. 61. Table dumps <ul><li>Similar structure to the flat-file tab delimited files </li></ul><ul><li>Why use this format? </li></ul><ul><ul><li>Use it to obtain the entire ChEBI database structure. </li></ul></ul><ul><li>Oracle binary dumps </li></ul><ul><ul><li>Import into an oracle database </li></ul></ul><ul><li>Generic SQL insert statements </li></ul><ul><ul><li>Import into MySQL or postgresql database </li></ul></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    62. 62. Web services <ul><li>Allow users to create their own applications to query data </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10 User application
    63. 63. The ChEBI web service <ul><li>Programmatic access to a ChEBI entry </li></ul><ul><li>SOAP based Java implementation </li></ul><ul><ul><li>Clients currently available in Java and perl </li></ul></ul><ul><li>Methods </li></ul><ul><ul><li>getLiteEntity </li></ul></ul><ul><ul><li>getCompleteEntity and getCompleteEntityByList </li></ul></ul><ul><ul><li>getOntologyParents </li></ul></ul><ul><ul><li>getOntologyChildren and getAllOntologyChildrenInPath </li></ul></ul><ul><ul><li>getStructureSearch </li></ul></ul><ul><li>Documented at http://www.ebi.ac.uk/chebi/webServices.do . </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    64. 64. Web service client object model ChEBI – Chemical Entities of Biological Interest 25.02.10 getLiteEntity getCompleteEntity getOntology (Parents and Children)
    65. 65. Methods and parameters (1) ChEBI – Chemical Entities of Biological Interest 25.02.10
    66. 66. Methods and parameters (2) ChEBI – Chemical Entities of Biological Interest 25.02.10
    67. 67. Methods and parameters (3) ChEBI – Chemical Entities of Biological Interest 25.02.10
    68. 68. Time for Exercises
    69. 69. For more information <ul><li>ftp://ftp.ebi.ac.uk/pub/software/webservices/Perl/WSChebiSOAPLite-2.0.zip </li></ul><ul><li>Email : [email_address] </li></ul><ul><li>SourceForge: https://sourceforge.net/projects/chebi/ </li></ul><ul><li>User Manual: http://www.ebi.ac.uk/chebi/userManualForward.do </li></ul><ul><li>RSS Feed </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    70. 70. Acknowledgements <ul><li>The ChEBI team </li></ul><ul><ul><li>Nico Adams Paula de Matos </li></ul></ul><ul><ul><li>Adriano Dekker Marcus Ennis </li></ul></ul><ul><ul><li>Janna Hastings Duncan Hull </li></ul></ul><ul><ul><li>Zara Josephs Steve Turner </li></ul></ul><ul><ul><li>Christoph Steinbeck </li></ul></ul><ul><li>Everyone @ the EBI and elsewhere who uses or contributes to ChEBI </li></ul><ul><li>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 &quot;Bioinformatics and biological resources&quot; fund. </li></ul>ChEBI – Chemical Entities of Biological Interest 25.02.10
    71. 71. Thank you

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