1. EBI is an Outstation of the European Molecular Biology Laboratory. Overview of ChEMBL Database Gareth Owen, ChEBI group, EMBL-EBI Northwestern University 16 th October 2012

2. What is ChEMBL? Open access database for drug discovery Freely available (searchable and downloadable) Content: 2D structures & calculated properties (logP, MW, Lipinski, etc.) Associated bioactivity data extracted from the primary medicinal chemistry journals such as J. Med. Chem. Deposited data from neglected disease screening (e.g. malaria) Subset of data from PubChem Covers ~30 years of compound synthesis and testing Annotated FDA-approved drugs Secure searching (https://www.ebi.ac.uk/chembldb )https://www.ebi.ac.uk/chembldb 2

3. ChEMBL Database Content 3 Assays are classified as: Binding measurements Functional assays ADME/toxicity data 60% proteins 20% organisms 20% cell lines ChEMBL14 Targets: 9,003 Compounds: 1,376,469 Activities: 10,129,256* Publications: 46,133 * Includes: ~5,900,000 (PubChem) ~100,000 (Deposited malaria screening sets) 3

4. ChEMBL Assays – Binding, Functional, ADMET Binding Assays Assays which directly measure the binding of a compound to a particular target E.g., competition binding assays with a radioligand Various endpoints measured, but most commonly reported are: IC50 (half maximal inhibitory concentration) Ki (binding affinity) MIC (minimum inhibitory concentration) % Inhibition (of activity) 4

5. Functional Assays Whole organism assays (e.g., anti-infectives/parasitics) Disease-derived cell-line (e.g., human ovarian cancer cell line cytotoxicity) Tissue or cell-based disease model (e.g., glucose uptake by adipocytes) Tissue or cell-based assay for target effect (e.g., contraction of guinea-pig ileum) Cell-based assay over-expressing target (e.g., GPCR calcium mobilisation) Target association Disease association 5

6. ADMET Assays Assays measuring: Absorption, Distribution, Metabolism, Excretion, Toxicity properties of compounds Examples include: Half-life of compound in rats Tissue distribution of compound Levels of metabolites 6

7. ChEMBL Targets: ProteinProtein complex Protein family Nucleic Acid e.g., Nicotinic acetylcholine receptor e.g., Muscarinic receptors Cell Line TissueSub-cellular Fraction Organism e.g., DNA e.g., Mitochondria e.g., Nervous e.g., HEK293 cellse.g., Drosophila e.g., PDE5 7

8. Protein Targets Each protein target linked to a sequence in UniProt Information from UniProt used in ChEMBL to allow searching: Protein name/description Synonyms and gene names Organism (and NCBI Tax ID) Proteins in ChEMBL also classified according to family (e.g., Receptor, Kinase, Protease, Transporter etc). Used for searching by target tree (Browse Targets) 8

9. ChEMBL Compounds Chemical structures are stored as.mol files If the stereochemistry is known it is drawn as a specific enantiomer Identifying unique compounds is done using standard Inchis Salts and parent molecules are grouped together for displaying bioactivity data although activity data is recorded against the specific salt 9 Tautomers of the same compound are treated as the same compound. The form shown is as in the paper

10. ChEMBL Home Page 10 https://www.ebi.ac.uk/chembldb

11. ChEMBL Main Search Page 11

12. 12 Small molecule resources at the EBI Clickable structure Drug Information Parent and Salt Forms

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14. 14 Click to display data

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17. 17 Parent and Salt Forms Database links

18. ChEBI Link: 18

19. This will take you back to ChEMBL 19

20. ChemSpider Links: 20 The link works both ways. They link TO ChemSpider and FROM ChemSpider. They link on Standard_Inchi

21. Wikipedia Links: 21 We also have links with Wikipedia. These also use the Standard_Inchi as the common identifier. These links will link to the Compound Report Card in ChEMBL. The links are added by a ChemoBot and can be updated with each release, if required.

22. Use Case 1 - Searching by Target What is known about chemical structures that bind to a specific protein (Adenosine A2a)? What is known about their potency/selectivity/ADMET Properties Is there any protein structure data? 22

23. Use Case 1 Searching by Target in ChEMBL Choose Sources to include in search 23

24. Retrieving Bioactivity Data - Single Target Bioactivity data for target Display all bioactivity data for target Click pie chart to retrieve particular end-points 3D StructuresAssay data for target 24

25. Filtering Bioactivities Select required activity types and define cut-offs e.g Ki<100nM Select targets of interest 25

26. Bioactivity Results Compound structures Target detailsActivity valuesAssay details References 26

27. Selectivity Data 27 For example: Can search ChEMBL for all data on compounds that have adenosine A2a Ki values <100nM

28. ADMET Data Summary of ChEMBL bioavailability data for compounds with A2a Ki values <100nM Example of Bioavailability data 28

29. Use Case 2 – Searching by Structure What compounds contain a particular substructure? What is known about their bioactivities? Known drugs/clinical Trials 29

30. 30 Different sketchers name Lists of Identifiers Types of synonyms: Research codes Trade names INN, USAN

31. Similarity and Substructure Searching 31 Display/Download Bioactivity Data

32. Filtering Data on Lipinski Properties etc 32 Display Bioactivities of subset 32

33. 33 namesStructureBioactivities

34. 34 BioactivitiesClinical TrialsPropertiesCross-references

35. Links to Other Resources 35

36. Links to Other Resources 36 PDBe - http://www.ebi.ac.uk/pdbehttp://www.ebi.ac.uk/pdbe

37. Marketed Drugs Select set of interest Export to Excel or Export SDF 37

38. Use Case 3 – Similar Targets Are there any available data on compounds that bind to proteins similar to IRAK2? For these compounds what bioactivity data is there on compounds with related sub-structures? Is there any crystal structure data on these proteins? 38

39. Protein Sequence Search More precise method for identifying targets Input is a protein sequence of interest Uses BLAST* algorithm to perform pair-wise comparisons between input sequence and all proteins in the Target Dictionary, to find most closely related matches Results are scored according to similarity to input sequence (determined by number of amino acids that are identical or have similar properties) *Altschul SF et al., J Mol Biol. 215(3), p403-10 (1990) 39

40. Data on IRAK1,IRAK3 and IRAK4 but not IRAK2 Use Case 3 – Similar Targets Protein Sequence of Interest e.g from UniProt http://www.uniprot.org 40

41. IRAK1, IRAK3 and IRAK4 data Identify sub-structure of interest What other data available on compounds with this sub-structure? 41

42. Use Case 4 - Assay keyword search Some ChEMBL data (e.g., functional assays) may not be mapped against molecular targets May want to perform a more general search (e.g., for a disease process, animal model, cell type of interest) Examples: 1.What compounds have been tested in disease models (cholesterol lowering)? 2.What data is available for brain penetration (brain to plasma ratio)? 42

43. Assay Search for “Cholesterol Lowering” 43

44. Assay Search for “Brain to Plasma” 44

45. Accessing ChEMBL Data 45

46. Useful Links 46 ChEMBL Blog: http://chembl.blogspot.com If you would like help: chembl-help@ebi.ac.uk For ChEMBL news and data releases subscribe to: http://listserver.ebi.ac.uk/mailman/listinfo/chembl-announce

47. Acknowledgements ChEMBL Group John Overington Anne Hersey Anna Gaulton Mark Davies Jon Chambers Louisa Bellis Kazuyoshi Ikeda Patricia Bento Shaun McGlinchey Yvonne Light Felix Krueger Ben Stauch Ruth Akhtar Francis Atkinson Rita Santos EMBL-EBI Samuel Kerrien, Sandra Orchard, Bruno Aranda, Rafael Jimenez, Reactome, UniProt and ChEBI teams Collaborators Imperial Cancer Research, University of Dundee, University of Cambridge, Sanger Centre, University of Maryland, NCBI, TDR, IUPHAR, Bayer-Schering, Pfizer, GSK, Schering-Plough, MMV, Novartis, St Jude Children’s Research Hospital Former Inpharmatica colleagues 47

48. 48 Exercises!

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