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Ideaconsult Ltd.

Ideaconsult Ltd. Dr. Nina Jeliazkova. Content. Introduction Main tasks in OpenTox Overview of the software developed by Ideaconsult ltd. Toxtree 1.51 Toxmatch 1.05 – A chemical similarity evaluation tool Ambit Discovery Ambit Database Tools 1.30 QMRF repository

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Ideaconsult Ltd.

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  1. Ideaconsult Ltd. Dr. Nina Jeliazkova OpenTox kick-off meeting Basel, Switzerland

  2. Content • Introduction • Main tasks in OpenTox • Overview of the software developed by Ideaconsult ltd. • Toxtree 1.51 • Toxmatch 1.05 – A chemical similarity evaluation tool • Ambit Discovery • Ambit Database Tools 1.30 • QMRF repository • Ambit XT new! Under development OpenTox kick-off meeting Basel, Switzerland

  3. Introduction • Ideaconsult Ltd is a SME registered with Sofia City Court at the end of 2004, providing consultancy, technical services and software development in the areas of chemoinformatics, QSAR and data mining; design and feasibility study of computer networks; support to governmental organizations, small and medium enterprises that require assistance in writing projects in IST and the Environment. • Develops and maintains several well-known and widely used open source software products, relevant to OpenTox, in particular • Toxtree (used in the application of the threshold of toxicological concern) • Toxmatch (for encoding and applying chemical similarity indices) • Ambit (a QSAR decision support system, including generic database management, structure conversions and searching, as well as applicability domain assessment). • These tools have been carefully designed and developed in close co-operation both with academia, regulatory bodies and industry. Some of the code base could be effectively re-used, adapted and further enhanced to meet the objectives of the project. OpenTox kick-off meeting Basel, Switzerland

  4. Main Tasks in OpenTox: • Work package 2 (Framework implementation) leader • Building blocks for a (Q)SAR decision support system (WP2) • Database for QSAR models (compliant with ECB QMRF) (WP2) • Work package 3 • AMBIT database with more than 450 000 chemical compounds (WP3) • Work package 4 • Chemoinformatics and data mining algorithms (WP4) • Algorithms for the determination of chemical similarities and applicability domains (WP4) OpenTox kick-off meeting Basel, Switzerland

  5. Toxtree 1.51 • Estimates toxic hazard by applying a decision tree approach. • Full-featured and flexible user-friendly open source software • New decision trees with arbitrary rules can be built with the help of graphical user interface or by developing new plug-ins in Java code • GPL license • Platform independent • Input: • datasets from various compatible file types • SMILES • built-in 2D structure diagram editor. • Output • SDF, MOL, CSV, MS Excel, CML, TXT, PDF, HTML • Batch mode • 5 classification schemes (plug-ins) for various endpoints assessment available OpenTox kick-off meeting Basel, Switzerland

  6. Toxtree 1.51 plug-ins: • Cramer rules(Cramer G. M., R. A. Ford, R. L. Hall, Estimation of Toxic Hazard - A Decision Tree Approach, J. Cosmet. Toxicol., Vol.16, pp. 255 -276, Pergamon Press, 1978); • Verhaar scheme for predicting toxicity mode of actions(Verhaar HJM, van Leeuwen CJ and Hermens JLM (1992) Classifying environmental pollutants. 1.Structure-activity relationships for prediction of aquatic toxicity. Chemosphere 25, 471-491); • A decision tree for estimating skin irritation and corrosionpotential, based on rules published in “The Skin Irritation Corrosion Rules Estimation Tool (SICRET), John D. Walker, Ingrid Gerner, Etje Hulzebos, Kerstin Schlegel, QSAR Comb. Sci. 2005, 24, pp378-384”; • A decision tree for estimating eye irritation and corrosionpotential, based on rules published in “Assessment of the eye irritating properties of chemicals by applying alternatives to the Draize rabbit eye test: the use of QSARs and in vitro tests for the classification of eye irritation, Ingrid Gerner, Manfred Liebsch & Horst Spielmann, Alternatives to Laboratory Animals, 2005, 33, pp. 215-237”; • A decision tree for estimating carcinogenicity and mutagenicity, based on the rules published in the accompanying document: “The Benigni / Bossa rulebase for mutagenicity and carcinogenicity – a module of Toxtree”, by R. Benigni, C. Bossa, N. Jeliazkova, T. Netzeva, and A. Worth. OpenTox kick-off meeting Basel, Switzerland

  7. Toxtree internalsSeries of questions are applied on query compound and also on reaction products Q1.Normal constituent of the body No Q2.Contains functional groups associated with enhanced toxicity No Q3.Contains elements other than C,H,O,N, divalent S No Q5.Simply branched aliphatic hydrocarbon or a common carbohydrate No Q6.Benzene derivative with certain substituents No Q7.Heterocyclic No Q16.Common terpene No Q17.Readily hydrolysed to a common terpene No Q19.Open chain No Q23.Aromatic Yes Q27.Rings with substituents Yes Q28.More than one aromatic ring Yes Q29.Readily hydrolysed Yes Query compound Hydrolysis products Q19.Open chain Yes Q20.Aliphatic with some functional groups Yes Q21.3 or more different functional groups No Q18.One of the list (see explanation) NoLow (Class I) Q30.Aromatic Ring with complex substituents No Q18.One of the list (see explanation) NoLow (Class I) OpenTox kick-off meeting Basel, Switzerland

  8. More on Toxtree • Structure alerts defined by SMARTS patterns • Descriptors calculation • LogP, Molar Refractivity, Partial MR, Sterimol, EHOMO, ELUMO, etc. • Explanations and examples for each rule outcome • Improved visualization and reporting • Can be embedded in other standalone and web applications • Recent publication: G. Patlewicz, N. Jeliazkova, R.J. Safford, A.P. Worth and B. Aleksiev, An evaluation of the implementation of the Cramer classification scheme in the Toxtree software, SAR and QSAR in Environmental Research, Vol. 19, Nos. 3–4, April–June 2008, 1–30 OpenTox kick-off meeting Basel, Switzerland

  9. Toxmatch 1.05 • Provides means to compare a chemical or set of chemicals to a toxicity dataset through the use of similarity indices • Intended use is one to many or many to many quantitative read-across • To help in the systematic formation of groups and read-across • Includes datasets for four toxicity endpoints to facilitate endpoint specific read-across • aquatic toxicity • bioconcentration factor • skin sensitisation • skin irritation • Developed under the terms of an Joint Research Centre (JRC) contract • Flexible open-source software application • Platform independent OpenTox kick-off meeting Basel, Switzerland

  10. Toxmatch 1.05 - methods • Structure representations • Descriptors • Fingerprints • Atom environments • Similarity indices (pair wise) • Euclidean distance • Cosine similarity • Hodgkin-Richards Index • Tanimoto distance • Tanimoto distance on fingerprints • Hellinger distance on atom environments • Maximum Common Structure similarity • Similarity to a set • Similarity between a query structure and a representative point of the set (e.g. the dataset centre or a consensus fingerprint) • Average similarity between a query structure and the nearest k structures • Descriptor generation • EHOMO, ELUMO, Log P, MW can be calculated • Verhaar and BfR skin irritation schemes as available in Toxtree are included G. Patlewicz, N. Jeliazkova, A. Gallegos Saliner, A. P. Worth, Toxmatch-a new software tool to aid in the development and evaluation of chemically similar groups,SAR and QSAR in Environmental Research, 19:3, 397 — 412(2008) OpenTox kick-off meeting Basel, Switzerland

  11. Toxmatch 1.05 - methods • Toxmatch is a promising tool to help in the systematic formation of groups and read-across • Possible to do quantitative read-across assessments using Toxmatch – either to predict the membership of a predefined group or to estimate the endpoint result using the weighted average of nearest neighbours as defined by a specific similarity index such as Euclidean distance or Tanimoto index • However toxicity data is required in order for analogues to be selected • There are of course limitations in encoding similarity into a single index – but that is less about the index per se and more about how we characterise the parameters for a given toxicity. An objective numerical measure can be helpful in grouping chemicals OpenTox kick-off meeting Basel, Switzerland

  12. AMBIT • Developed within the framework of CEFIC LRI project “Building blocks for a future (Q)SAR decision support system: databases, applicability domain, similarity assessment and structure conversions”. • Consists of a relational database and functional modules allowing a variety of evaluations flexible structure, similarity and other queries. • Applications: • Ambit Database tools 1.30 (on the right) • Ambit Discovery (applicability domain assessment) • Ambit Online OpenTox kick-off meeting Basel, Switzerland

  13. AMBIT DiscoverySoftware for applicability domain assessment • Methods: • Ranges • Euclidean distance • City-block Distance • Probability Density • Fingerprints • Consensus fingerprint + Tanimoto distance • Consensus fingerprint + Missing fragments • Atom environments • Consensus atom environments + Hellinger distance • kNN + Tanimoto distance • Ranking • More options • Threshold • Preprocessing (e.g. PCA) • Center • Results from multiple methods are automatically combined. Joanna Jaworska, Nina Nikolova-Jeliazkova, How can structural similarity analysis help in category formation, SAR and QSAR in Environmental Research, vol 18, 3-4 (2007) OpenTox kick-off meeting Basel, Switzerland

  14. AMBIT Extensions • ECB commissioned an extension to develop a reference site for retrieving robust summaries of (Q)SAR models in QSAR Model Reporting Format (QMRF) • AMBIT XT – under development OpenTox kick-off meeting Basel, Switzerland

  15. AMBIT XT • Built upon AMBIT software • Objectives: • Develop an open source user friendly software, providing a set of functionalities to facilitate registration of the chemicals for REACH. • Improve the user friendliness by introduction of workflow capabilities • Develop a set of defined workflows for analogue identification and PBT assessment. • Close collaboration with industry • LGPL license OpenTox kick-off meeting Basel, Switzerland

  16. AMBIT XT emphasize on • Data provenance • history of the updates of the chemicals information. • Data quality • Easy way for comparison between different sources • Flexible storage for measured data for different endpoints • Easy way to extract all relevant information for a chemical; many formats available for toxicological data • Recording of user actions • Easy entry of complex structural alerts to facilitate grouping • Molecular descriptors • Improved data entrance and visualization • Embedded workflow engine • Modular application (flexible plug-in support) OpenTox kick-off meeting Basel, Switzerland

  17. Thank you! OpenTox kick-off meeting Basel, Switzerland

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