1. Open PHACTS Easy API Community Workshop, June 25, 2014 Christine Chichester Swiss Institute of Bioinformatics

2. Concepts Data Sources Use Cases API Approach for analysis

3. “Find me compounds that inhibit targets in NFkB pathway assayed in only functional assays with a potency <1 μM” “What is the interaction profile of known p38 inhibitors?” “Let me compare MW, logP and PSA for known oxidoreductase inhibitors” Use Cases

4. Concepts Data Sources Use Cases API Approach for analysis

5. Concepts Chemical compounds Biological targets Pathways Diseases

6. Concepts Data Sources Use Cases API Approach for analysis

7. ChEMBL DrugBank Gene Ontology Wikipathways UniProt ChemSpider ChEMBL Target Class ChEMBL Target Class ConceptWik i ChEBI DisGeNet neXtProt Data Sources ENZYME FDA adverse events FDA adverse events Clinical trials.org

8. Concepts Data Sources Use Cases API Approach for analysis

9. Registering for API keys API Overview Entry Points: URLs API Results Getting Started with Compounds Going Further Open PHACTS API Basics

10. Get my API keys! https://dev.openphacts.org/admin

14. API Overview: Documentation https://dev.openphacts.org/docs/1.3

15. The Linked Data API – Simple Rest-ful API Advantages of the linked data approach while providing a more familiar API Lowers the barrier to data access Based on community standards REST JSON, XML, TSV Not just data access, but complex queries allowing filtering, pagination, export, etc.

17. Response template legend for API calls results

18. 1.3 API calls: Concept types

19. Multiple result formats

20. Many filtering options per call

21. Calls that provide filtering parameters

22. API Entry Points: URLs https://dev.openphacts.org/docs/1.3

23. What’s needed to get started? The API is URL centric -http://rdf.chemspider.com/906 -http://www.conceptwiki.org/concept/60915889-bbea-4c10- a810-7dfd6eb05168 Why? -Ensures precise identification of the concept -Allows for dereferencablity -supports many URLs from different domains Next: Getting a URL

24. Finding an initial URL

25. Compound example: Naphthalene Textual name: Naphthalene SMILES: C1=CC=C2C=CC=CC2=C1 InChI: InChI=1S/C10H8/c1-2-6-10-8-4-3-7-9(10)5-1/h1-8H

27. "_about": "http://www.conceptwiki.org/concept/60915889-bbea-4c10-a810-7dfd6eb05168”

29. Entry with either Chemspider or ConceptWiki URL (or others) into other API calls "_about": "http://rdf.chemspider.com/906"

30. API Results: Example with Compound APIs

31. Compound APIs: Results by Dataset Chembl DrugBank OPS: Open PHACTS Chemical Registry “inDataset”

32. Compound Pharmacology API: Retrieve a target URL Target URL

33. Target Information API: Using target URL from previous call Target URL

34. Target Information API: results (continued)

35. Compound -> Target in 3 URLs 1.Free text to retrieve a compound URL 1.Pharmacology for the compound: results include a target URLs 1.More information about a target

37. Thank you

38. Solving more use cases

39. 1.) Provide all activities for a given compound X, with targets annotated by gene (Compound -> target) needed API calls: –Compound Pharmacology Paginated –Map URL

40. Compound Pharmacology Paginated – parameters uri: needs a compound uri. Possible sources: –Map free text to a concept URL methods –SMILES, Inchi or InchiKey to URL methods –Chemical Structure search methods –known identifier from other sources: e.g. http://www.chemspider.com/2157, http://rdf.ebi.ac.uk/resource/chembl/molecule/CHEMBL25, –http://en.wikipedia.org/wiki/Aspirin app_id and app_key target_type: single_protein (if wanted) _pageSize (default 10, use with loop on _page, or set to all)

41. Compound Pharmacology - results

42. Retrieving a protein/gene ID Use the Map URL API call Uri: any input uri, e.g. http://rdf.ebi.ac.uk/resource/chembl/target/CHEMBL221 (Restrict to wanted targetUriPattern) Example results: –http://www.ncbi.nlm.nih.gov/gene/5742 –http://www.uniprot.org/uniprot/P23219

43. 2.) Provide all compounds assayed for target Y with target indicated by a gene (Target -> Compound) needed API call: –Target Pharmacology Paginated input parameter: –uri: protein or gene uri, e.g. http://www.ncbi.nlm.nih.gov/gene/5742

45. 3.) For target X provide target family. (Gene -> Gene family) needed API calls: –Target Classifications parameters for classification: –tree: chembl, enzyme or go

46. Retrieving Pharmacology for all proteins with a given classification Target Class Pharmacology Paginated –uri: Classification uri e.g. http://purl.uniprot.org/enzyme/1.14.99.1http://purl.uniprot.org/enzyme/1.14.99.1

47. 4.) Filter results by activity cut-offs Available filters: –Activity type / cutoff value / units combinations –pChembl cutoff values –activity relation filters (>, >=, =, <, <=) –Organism filters (target and assay organism) –Target type (e.g. single_protein, protein_family)

48. STANDARD_TYPE UNIT_COUNT ---------------- ------- AC50 7 Activity 421 EC50 39 IC50 46 ID50 42 Ki 23 Log IC50 4 Log Ki 7 Potency 11 log IC50 0 STANDARD_TYPE STANDARD_UNITS COUNT(*) ------------------ ------------------ -------- IC50 nM 829448 IC50 ug.mL-1 41000 IC50 38521 IC50 ug/ml 2038 IC50 ug ml-1 509 IC50 mg kg-1 295 IC50 molar ratio 178 IC50 ug 117 IC50 % 113 IC50 uM well-1 52 IC50 p.p.m. 51 IC50 ppm 36 IC50 uM-1 25 IC50 nM kg-1 25 IC50 milliequivalent 22 IC50 kJ m-2 20 ~ 100 units >5000 types Implemented using the Quantities, Dimension, Units, Types Ontology Quantitative Data Challenges

49. Activity type / cutoff value / units combinations possible values: –Activity types: e.g. Potency, GI50, IC50, Ki, … –cutoff values: number with the appropriate parameter –= activity_value –>= min-activity_value –> minEx-activity_value –<= max-activity_value –< maxEx-activity_value –Units for activity type: e.g. nanomolar, microgram_per_milliliter

50. pChembl cutoff values Definition: -Log(molar IC50, XC50, EC50, AC50, Ki, Kd or Potency) –e.g. IC50=10µM -> pChembl = 5 Filters: –= pChembl –>= min-pChembl –> minEx-pChembl –<= max-pChembl –< maxEx-pChembl

51. 5.) Substructure and Similarity search in Open PHACTS. Uses Chemspider search tools (Bingo from GGA) Chemical Structure Exact/Similarity/Substructure Search

52. Chemical Structure Similarity Search selected parameters: –searchOptions.Molecule: a SMILES string –searchOptions.SimilarityType: 0: Tanimoto; 1: Tversky; 2: Euclidian –searchOptions.Threshold: value between 0 and 1 –resultOptions.Count: number of results

53. 6.a) For a target Y, find pathway Z Needs API call: –Pathways by Target Find an identifier for the target –http://www.conceptwiki.org/concept/2e754389-d9d4- 4c93-8046-f03722573946http://www.conceptwiki.org/concept/2e754389-d9d4- 4c93-8046-f03722573946 Additional: Map URL, possibly with the restriction http://identifiers.org/ncbigene/ or http://identifiers.org/ensembl/ to retrieve complementary identifiers http://identifiers.org/ncbigene/ http://identifiers.org/ensembl/ Additional: Count Pathways by Target

54. "_about": "http://rdf.wikipathways.org/Pathway/WP710_r67156", "identifier": "http://identifiers.org/wikipathways/WP710", "title": "DNA damage response (only ATM dependent)", "description": "This is the second pathway out of two pathways which deals with DNA damage response", "hasPart": { "_about": "http://identifiers.org/ensembl/ENSG00000135679", "type": "http://vocabularies.wikipathways.org/wp#GeneProduct", "exactMatch": { "_about": "http://www.conceptwiki.org/concept/2e754389-d9d4-4c93- 8046-f03722573946", "prefLabel": "E3 ubiquitin-protein ligase Mdm2 (Homo sapiens)" } }, "inDataset": "http://www.wikipathways.org", "pathway_organism": { "_about": "http://purl.obolibrary.org/obo/NCBITaxon_9606", "label": "Homo sapiens" }, Pathways by Target

55. "_about": "http://www.conceptwiki.org/concept/2e754389-d9d4-4c93-8046- f03722573946", "exactMatch": "http://identifiers.org/ncbigene/4193”, "http://identifiers.org/ensembl/ENSG00000135679", Map URL with restriction on namespace

56. 6.b) For a pathway Z, find target Y Needs API call: –Get Targets for Pathway, textually names for pathways can be searched (Map free text to concept URL) or use WikiPathway URI directly: http://www.conceptwiki.org/concept/ad73ac9e-f606-4ea9- b357-3eed6f837ca8http://www.conceptwiki.org/concept/ad73ac9e-f606-4ea9- b357-3eed6f837ca8 http://www.wikipathways.org/instance/WP710

57. "_about": "http://rdf.wikipathways.org/Pathway/WP710_r67156", "title_en": "DNA damage response (only ATM dependent)", "title": "DNA damage response (only ATM dependent)", "hasPart": [ "http://identifiers.org/ncbigene/7476", "http://identifiers.org/ncbigene/7481", "http://identifiers.org/ncbigene/8061",… List of genes/proteins in pathway Get Targets for Pathway