1. AMBIT Chemoinformatics Software for Data Management Joanna Jaworska Nina Jeliazkova P&G Brussels, Ideaconsult Ltd., Belgium Bulgaria

2. Introduction – why Ambit ? Limited free, publicly accessible, methodologically transparent software was identified as one of the roadblocks for broadening use of in-silico methods (ICCA Workshop in Setubal 2002, OECD) Realization that efficient use of existing information on chemicals requires better ways for Storage −standardized formats, computer automated verification of structures, capability to store large amounts of data Taking advantage of rapidly evolving field of data mining and extraction of relevant information

3. IT strategy Ambit - building blocks for Decision Support System High emphasis on interoperability for “plug and play” −Chemical Markup Language (CML) acknowledged method of encoding chemical data in XMLacknowledged method of encoding chemical data in XML Is being adopted by a large number of chemical organisations, from government, through commercial to academia.Is being adopted by a large number of chemical organisations, from government, through commercial to academia. The choice of CML for the internal format makes the database independent of the software which is able to access it, in contrast to some proprietary solutions.The choice of CML for the internal format makes the database independent of the software which is able to access it, in contrast to some proprietary solutions. Flexibility modular design Transparency −Open source, relying on open standards. Open source software lowers the user barrier, facilitates the dissemination activities and enables the reproducibility of models and results −The cheminformatics functionality relies on the open source Java library – The Chemistry Development Kit http://cdk.sourceforge.net/http://cdk.sourceforge.net/ −The software is based on MySQL database (www.mysql.com), which is the most popular open source relational database.www.mysql.com

4. Ambit - Overview AMBIT software is a set of libraries and tools, providing various cheminformatics functionalities for data management. The AMBIT system consists of a database and functional modules allowing a variety of flexible searches and mining of the data stored in the database. The unique feature of AMBIT is the ability to store multifaceted information about chemical structures and provide a searchable interface linking these diverse components. The AMBIT database: AMBIT database contains over 450 000 chemical compounds with data imported from over a dozen databases [http://ambit.acad.bg/ambit/stats/]. The number of compounds is growing all the time and one the of system’s great strengths is that any dataset can be imported for comparison and analysis. stores chemical structures, their identifiers such as CAS, INChI numbers; attributes such as molecular descriptors, experimental data together with test descriptions, and literature references. The database can also store QSAR models. In addition the software can generate a suite of 2D and 3D molecular descriptors. can be searched by identifiers, attribute value or range, experimental data value or range, user defined structure and substructure, structural similarity AMBIT Discovery performs chemical grouping and assesses the applicability domain of a QSAR offering a variety of methods including using different approaches to similarity assessments: statistical that rely on ‘descriptor space’; approaches based on mechanistic understanding; and approaches based on structural similarity.

5. Software build using Ambit blocks ToxTree ToxTree is a flexible user friendly application which integrates structure based (classification) schemes. Currently 3 schemes are available: Verhaaar for fish toxicity, Cramer for human acute toxicity, BfR rules for skin irritation. ToxTree implements a plug-in mechanism, allowing to be extended by modules developed at a future time, without recompiling the application. ToxTree and AMBIT modules can be integrated one within another. Toxmatch – stand alone application for pairwise similarity assessments with intention for read-across. QSAR database under development. Will store information in QMRF. Large effort on standardization

6. Ambit database - Two user interfaces Two user to the database Online Standalone Online a more restricted interface Standalone Full interface Can be used for storing & managing confidential data Common Can link with other databases and pull information via webservices

7. AMBIT Database Today Not restricted to these datasets!Any dataset can be imported. (e.g. DSSTox, AQUIRE, LLNA …)

8. AMBIT Database Schema

9. Experimental results repository

10. AMBIT database functionalities Storage: information about chemicals name and structure, descriptors, experimental data and QSAR models Example with a tailored template : BCF golden database LRI project ( EURAS) Q2 2007 QSAR database with QMRF ( ECB funded) Conversion: Different computer formats of structure, CAS-structure Calculation Variety of descriptors, The available list is growing thanks to contributions to CDK Search identification search (CAS, SMILES, chemical name) Descriptor search Experimental data search Substructure and similarity search Complex searches with multiple criteria (standalone)

11. Similarity searching Rationale based on the Similar property Principle: structurally similar compounds tends to exibit similar properties Calculate the pairwise similarity between the know active and each compound in the database Rank the database compounds based on similarity measure Select top n% for biological testing

12. What kind of searches are desired ? Detailed analyses for pairwise similarity Similarity of a compound to compounds in the database Similarity of a compounds to a reference set Similarity of a set of compounds to compounds in the database Grouping based on chemical class

13. Ambit online Searching for basic information

14. AMBIT Online: Similarity search

16. AMBIT Online: Query result

17. Links to other databases: (example: KEGG)

18. Link to Aquire

19. Information about QSAR models

20. Ambit Database Tools 1.20 Standalone application available at http://ambit.acad.bg/downloads

21. Ambit converter (Batch search) Ambit converter can open : CML, CSV, HIN, ICHI, INCHI, MDL MOL, MDL SDF, MOL2, PDB, SMI, TXT and XYZ file types Ambit converter can save : SDF, MOL, CSV, TXT, SMI file types. CAS-SMILES conversion based on a database lookup Descriptors calculation Cramer rules, Verhaar scheme

22. Ambit Database Tools 1.20 Import to Database Compounds – several file formats Descriptors – SDF, CSV, TXT Experimental data – SDF, CSV, TXT QSAR models – SDF, CSV, TXT Database processing Calculate SMILES/Fingerprints/Atom environments – necessary in order to perform substructure and similarity search. Should be invoked after importing compounds into database several file formats Descriptors calculation Distances calculation – used to speed up distance between heavy atoms query

23. Ambit Database Tools 1.20 perform a CAS RN search in the database (submenu "Search -> CAS RN search"); perform a SMILES search in the database (submenu "Search -> SMILES"); perform a molecular formula search in the database (submenu ("Search -> Molecular formula"); define structure,descriptor,distance-based and experimental data criteria and perform searches in the database database Output: On screen To file The user can select between the different datasets existing in the AMBIT database. Subsequent searches will be performed only within the selected dataset

24. AMBIT User Interface Example: Search by structure Exact search Substructure search Similarity search Fingerprints Atom environments

25. AMBIT User Interface Example: Search by descriptors

26. AMBIT User Interface Example: Search by experimental data

27. Similarity based on toxicity mechanism Verhaar scheme Verhaar H.J.M., Van Leeuven C., Hermens J.L.M.,Classifying Environmental Pollutants. 1: Structure-Activity Relationships for Prediction of Aquatic Toxicity, Chemosphere, Vol.25, No.4, pp.471-491, 1992 34 rules 5 classes Class 1. Narcosis or baseline toxicity Class 2 Less inert compounds Class 3 Unspecific reactivity Class 4 Compounds and groups of compounds acting by a specific mechanism Class 5 Not possible to classify according to these rules

29. Chemical similarity assessment using the database Exact substructure search based on 2D Structural Similarity search (various methods) Criteria on descriptors Based on mechanistic understanding ( Verhaar scheme)

30. Another view on Similarity assessments with Toxmatch and Discovery Discovery similarity to a set (summary representation) Toxmatch pairwise similarities Similarity to a set (nearest neighbours)