AMBIT Cheminformatics system

Transcription

1 1 Workshop on CEFIC LRI Project EEM9.4 LRI AMBIT with IUCLID6 support and extended search capabilities AMBIT Cheminformatics system Nina Jeliazkova, Nikolay Kochev Ideaconsult Ltd. Sofia,Bulgaria

2 2 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Content Introduction Substance data integration in AMBIT ( different input formats) Search functionalities - Structures, substances and endpoint data - Structure standardization, transformation, tautomers Tools integration via common API - Toxtree, VEGA, other models, descriptors User management system to grant access rights via roles The read across workflow - An use case integrating the above functionalities IT requirements

3 AMBIT Chemoinformatics System Developed within a CEFIC Long-Range Initiative (LRI) EEM9.3 (2005,2008), EEM9.3-IC ( ), EEM9.4 (2016-ongoing) Continuously developed and extended through various projects An Open Source Application with the following functions Search for structure(s) [exact, similar, substructure] and meta data Assigning structures to constituents, impurities Assessment tools (read across/category formation) Prediction tools e.g. Toxtree (including Cramer rules, Protein binding, etc.), descriptor calculation, pka etc; Data analysis tools e.g. regression, classification, clustering etc; Data management : flexible import/export of data Data exchange tools: manual or automated via REST Web services API; Read across workflow 3

4 AMBIT: Chemical structures database & machine learning with web services API 4

5 AMBIT : Data integration via common data model Excel spreadsheets IUCLID5 IUCLID6 Other formats Free text search Reports (Excel, Word) Other formats (RDF, ISA-TAB, etc.) JSON REST API ambitlri.ideaconsult.net

6 6 AMBIT2 Hands-on Training Workshop , Brussels, Belgium IUCLID6 support in AMBIT2 IUCLID6: Completely new XML schema of all objects schema files, 111 endpoint study record files - Different approach of linking between objects (compared to IUCLID5) Implementation - Java classes generated from the XML schema (via JAXB) - AMBIT code to convert the generated classes to the internal data model and be able to store into the database - Use existing code for writing into the database - And existing UI to show the data Transparent from user point of view: select.i6z or.i5z

7 7 Spreadsheets for substance data import configurable parser for spreadsheet data templates

8 8 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Excel files Not only chemical structures and data Relationships between structures Imported into AMBIT database with the help of a JSON configuration EFSA OpenFoodTox data

9 9 Ideaconsult Ltd. Search substances by endpoint data Check one or more checkboxes and click the Update results The endpoints are combined by AND. Endpoints are grouped in four categories P-Chem, Env Fate Eco Tox, Tox The results above show there are only two substances having data for the three selected endpoints (Appearance, Melting point and Dissociation constant), although there are 16 substances with data for appearance, 36 substances with melting point values and 15 substances with dissociation constant

10 10 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Free text search (experimental)

11 AMBIT Search for Structures & Endpoint data 1) Find Structure(s) 2) Find Substance(s) 3) Display data 11

12 Combining information from other data sources and prediction results The vertical sidebar allows collating data and model information with the search results.

13 13 Ideaconsult Ltd. Structure Diagram Editor Click to show/hide the editor The structure editor is JavaScript based. To use the drawn structure for search, click the Use button. To show the structure, specified as SMILES in the search bar, click the Draw button.

14 14 Ideaconsult Ltd. Substructure search The substructure search query can be defined by drawing the structure, selecting a SMARTS from the predefined list of SMARTS, or entering a SMARTS, SMILES or chemical name in the text box

15 15 Ideaconsult Ltd. Substance tab Use the folder icon to open the details. The Substanc es tab shows the substances related to the chemical structure, and the role of the chemical structure (last column, e.g. Constituent, Impurity, Additive).

16 16 Enabling Structure Search : Structure Standardization conversion to implicit hydrogens keep the largest fragment kekulisation Na + O - Na + O - O - O - N H 2 O N H 2 O N H 2 O N H 2 O (i) molecule neutralization OH structure conversion to a canonic tautomer (ii) Custom reaction transformations OH Isotopes cleanup OH HN O N H 2 O N H 2 O Output: smiles, InChI N=CCCCC(=O)O InChI=1/C5H9NO2/c (7)8/h4,6H,1-3H2,(H,7,8)

17 17 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Canonic tautomer generation (a component of the standardisation procedure) Input structure N H 2 OH O Rule instance search N H 2 OH O Generation of all tautomers: H 2 N OH OH OH OH HN OH Canonical Ranking O HN OH O 0.0 C(C=CN)C=C(O)O -0.1 C(C=CN)CC(=O)O C(CC=N)C=C(O)O C(CC=N)CC(=O)O N H 2 HN OH O

18 18 Ideaconsult Ltd. Automatic generation of all tautomeric forms of a given organic compound. Customizable rules for tautomeric transformations. The predefined knowledge base covers 1 3, 1 5 and 1 7 proton tautomeric shifts. Typical supported tautomerism rules are keto-enol, imin-amin, nitrosooxime, azo-hydrazone, thioketo-thioenol, thionitroso-thiooxime, amidine-imidine, diazoamino-diazoamino, thioamide-iminothiol and nitrosamine-diazohydroxide Simple energy based system for tautomer ranking implemented by a set of empirically derived rules.

19 Recursion 19 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Input structure AMBIT TAUTOMER Rule selection and flag settings OC(O)=C(N)C Structure is removed Post-generation filtering Ranking Generating of tautomeric forms: - Combinatorial method - Combinatorial method improved - Incremental method (IA-DFS) Result Canonical I D E A C O N S U L T L T D. 19

20 20 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Structures transformation : AMBIT SMARTS/ SMIRKS (1) Efficient representation of SMARTS Queries (full Daylight syntax) (2) Fast structure isomorphism /mapping/ (3) Support of recursive SMARTS and stereo (4) Syntax extensions (5) Parsing of SMIRKS (6) Transformation of the target chemical objects Transformations modes: (1) single (2) non-overlapping, (3) non-identical, (4) non-homomorphic or (5) externally specified list of sites. Recursive expressions explicitly define the environment around S atom.

21 21 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Structure standardization in large datasets Flexible standardisation workflow - The rules synchronised with pharma companies Datasets standardised with AMBIT ( H2020 FET ExCAPE project) - PubChem,ChEMBL,eMolecules,SureChem,ZINC,tox datasets ( > 80 mln compounds) ExCAPE DB (1 mln compounds, 70 mln SAR data points), AMBIThosted, open access - Possible future integration with LRI AMBIT

22 Communications with other systems Transfer via Web service or *.i6z files Data transfer Other Databases Company IUCLID DB & ECHA IUCLID DB as Major Data Sources LRI AMBIT Supporting Read across & Category formation Transfer of Dossiers Data transfer Data transfer Other Tools 22

23 AMBIT Web API /UI for data analysis Dataset Models Visualisation

24 AMBIT Web API / UI for data analysis Descriptor calculation, feature selection; Classification and regression algorithms; Rule based algorithms; Applicability domain algorithms; Visualization, similarity and substructure queries ; Composite algorithms (workflows); Structure optimization (MOPAC), metabolite generation, tautomer generation, etc. 24

25 25 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Integration with external tools Command line java application provided by IRFMN

26 26 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Integration with external tools : VEGA REST model wrapper Same API as other models (e.g. Toxtree) Same user interface Predictions automatically stored Straightforward integration with read across matrix

27 27 Ideaconsult Ltd. AMBIT users management The authorization is role based. Default roles: user, data manager, admin, read-across Roles can be assigned at the users page by admin user

28 28 AMBIT2 Hands-on Training Workshop , Brussels, Belgium Restricted access to assessments

29 29 AMBIT2 Hands-on Training Workshop , Brussels, Belgium The read across workflow: integrated view of data and predictions

30 AMBIT publications and contributing projects Peer reviewed publications (excerpt) 1. J. Sun, N. Jeliazkova, et al, ExCAPE-DB: an integrated large scale dataset facilitating Big Data analysis in chemogenomics, J. Cheminform., vol. 9, n. 1, p. 17, Mar N. Jeliazkova, et al, The enanomapper database for nanomaterial safety information, Beilstein J. Nanotechnol., vol. 6, pp , Jul N. Kochev, V. Paskaleva, and N. Jeliazkova, AMBIT- Tautomer: An open source tool for tautomer generation, Mol. Inform., vol. 32, pp. 1 24, N. Jeliazkova and V. Jeliazkov, AMBIT RESTful web services: an implementation of the OpenTox application programming interface, J. Cheminform., vol. 3, no. 1, p. 18, Jan CEFIC LRI EEM9.3 P&G (J.Jaworska), Nina Jeliazkova CEFIC LRI EEM9.3-IC, EEM9.4 (ongoing) : IdeaConsult Ltd., UM, Clariant Projects contributed to the development EC FP7 OpenTox ( ) EC FP7 ToxBank ( ) EC FP7 enanomapper ( ) EC H2020 ExCAPE ( ) (and more) 5. N. Jeliazkova, J. Jaworska, and A. Worth, Open Open source libraries Source Tools for Read-Across and Category Formation, in In Silico Toxicology, M. Cronin and J. The Chemistry Development Kit Madden, Eds. Cambridge: Royal Society of (and many more) Chemistry, 2010, pp

31 can be downloaded or consulted online: Publicly available - Clients only need a web browser More information and download links - Installation options LOCAL on a LAPTOP/DESKTOP - Local database, local webserver SERVER (on company INTRANET) - Shared database and web server. Clients only need a web browser. Requirements - Java 7, MySQL 5.7, Web server (servlet container, e.g. Apache Tomcat 7.x) TECHNICAL SUPPORT contact Ideaconsult Ltd, Sofia support@ideaconsult.net 31

32 Acknowledgements CEFIC LRI EEM9.3-IC/EEM9.4 o Bruno Hubesch Project idea for LRI EEM9.3-IC o Volker Koch, Clariant Project input : Clariant CompTox Team o Udo Jensch (Toxicologist) o Volker Koch (Ecotoxicologist) o Qiang Li (Toxicologist) o Joachim Schneider-Reigl (Ecotoxicologist) Project implementation Ideaconsult Ltd. 32

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