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1 248th American Chemical Society National Meeting & Exposition The use of any device to capture images (e.g., cameras and camera phones) or sound (e.g., tape and digital recorders) or stream, upload or rebroadcast speakers or presentations is strictly prohibited at Services Research Training Industry all official ACS meetings and events without the express written consent from the ACS. NO RECORDING PLEASE

2 ChEMBL - Linking chemistry and biology to enable mapping onto molecular pathways Louisa Bellis Chemical Content Curator, ChEMBL Database EMBL-EBI, UK ACS 10 th -14 th August 2014 Services Research Training Industry

3 Drug discovery From discovering a target to a drug reaching the market: 12 years. Bioinformatics shortens time to target discovery. EMBL-EBI services support all stages of drug discovery.

4 Data resources at EMBL-EBI Genes, genomes & variation European Nucleotide Archive 1000 Genomes Ensembl Ensembl Genomes European Genome-phenome Archive Metagenomics portal Gene, protein & metabolite expression Literature & ontologies Europe PubMed Central Gene Ontology Experimental Factor Ontology ArrayExpress Expression Atlas Metabolights PRIDE Protein sequences, families & motifs InterPro Pfam UniProt Molecular structures Protein Data Bank in Europe Electron Microscopy Data Bank Chemical biology Reactions, interactions & pathways IntAct Reactome MetaboLights ChEMBL Systems BioModels Enzyme Portal ChEBI BioSamples

5 What is the ChEMBL database? Open access data for drug discovery Core of database is the primary Med Chem literature, covering over 33 years of research inc: J. Med. Chem., Bioorg. Med. Chem. Lett., Science Data-sharing arrangement with PubChem Contributed datasets Mainly NTD, GSK kinase set, TG-Gates, DNDi etc Marketed Drugs Mostly FDA OrangeBook, Dailymed etc

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7 Data Statistics Small Molecules Peptides Biotherapeutics Compound Content Abstracted from 57,156 papers across 47 journals 1,411,786 compounds (~450,000 from PubChem) 12,843,338 activities (>6.0 million from PubChem) binding measurements, functional assays and ADMET 10,579 targets, inc. > 5,400 protein targets and over 2,900 human targets.

8 ChEMBL Target Types Molecular Non-molecular Nucleic acid Protein Cell-line Tissue Subcellular-fraction Organism DNA HEK293 cells Nervous Mitochondria Drosophila Single Protein Protein Complex Protein Family PDE5 Nicotinic acetylcholine receptor Muscarinic receptors

9 Bioactivity measurements > 5000 different endpoint types (e.g., Ki, LD50, heart rate change, sleep time, growth inhibition) Standardisation of endpoints and units Standardisation of endpoints and mapping to BAO Half-life, Elimination half-life, t1/2 -> T1/2 -> BAO_ Conversion of concentrations to nm Anti-logging of log data pic50 = 9 -> IC50 = 1nM pchembl values for simple comparison -Log(molar IC50, XC50, EC50, AC50, Ki, Kd or Potency)

10 pchembl

11 MAPPING TO PATHWAYS

12 Compound Report Card

13 Compound Report Card

14 Target Browsing & Searching Target Name

15 Target Browsing & Searching

16 Target Report Card

17 Target Report Card

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19 For performing more general search (e.g., for a disease process, animal model, cell type of interest)

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21 For specific pathway searching: OPRM1

22 Search for OPRM1 in ChEMBL

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24 Compounds linked to activity for OPRM1

25 Overlay ChEMBL Compounds that interact with Pathway

26 EBI RDF Platform

27 ChEMBL RDF Compound Bioactivity Assay Target Ref ftp://ftp.ebi.ac.uk/pub/databases/chembl/chembl-rdf/

28 Federated (cross-database) queries Reactome proteins + drug-like molecules

29 Proteins in pathway interacting with drug-like cmpds Caspase-8 34 TNF-alpha 12 TNF-R1 7 RIPK1

30 ADME SARFARI

31 Homepage Keyword Search Components Molecule Search Protein BLAST Search Submit molecule to ADME Target Model Prediction Submit molecule to substructure/similarity search Run BLAST Search FASTA Lookup

32 Target Model Search Aim: Identify ADME protein targets which may bind and possibly metabolise user submitted structure User can draw, upload or drag n drop a structure Click this button to submit structure to model

33 Model Search Workflow Default Results Page: Orthologues* *Orthologue page default colouring changes when running a model search. Targets are coloured green when predicted to bind user submitted compound structure. Related Target Bioactivities Protein Tissue Expression Query Related Compounds Pharmacokinetics Overview

34 Rows = Orthologues Groups Orthologues All Data Filter table by organism, source, class (Phase I, Phase II, Transporter,..) Export Data Columns = Organism Link to Target Report Card Link to Orthologue Group overview page alignments, variation data, external links

35 Bioactivities All Data Hide/Show Extra Columns Export Data All ChEMBL ADME Related Bioactivity Data

36 CROP PROTECTION DATA

37 Crop Protection Data Collaboration with Syngenta in adding crop protection data Project to extract and incorporate additional insecticide, fungicide and herbicide bioactivity data 2,444 articles of interest identified through combination of text-mining and prioritisation by Syngenta 245,370 activity data points 34,940 distinct compound structures Of which 28K are new to ChEMBL

38 Data Content Target Organisms

39 Data Content Target Organisms Additional crop protection data set contains: 441 plant targets (organism/tissue/protein targets) 71 protein targets (all species) 326 fungal targets (organism/tissue/protein targets) 17 protein targets (all species) 281 insect targets (organism/tissue/protein targets) 50 protein targets (all species)

40 ChEMBL Integration + Future Plans Crop protection data incorporated into ChEMBL_19 release Look into feasibility of adding new data in future releases Enhanced mechanisms for searching/filtering crop protection data Improved organism classification and standardisation of endpoints

41 Help and Feedback addresses for support queries and feedback General questions and feedback on ChEMBL interface: Reporting of data errors:

42 Acknowledgements ChEMBL John Overington Francis Atkinson Patricia Bento Jon Chambers Mark Davies Nathan Dedman Anna Gaulton Anne Hersey Michal Nowotka George Papadatos José Bach Hardie Samuel Croset Felix Krueger Grace Mugumbate Rita Santos Crop Protection Data Namrata Kale (assay curation) Gerard van Westen (identification of relevant papers)

43 Thank you Any questions? Services Research Training Industry