Transcript Ideaconsult Ltd.

Ideaconsult Ltd.
Dr. Nina Jeliazkova
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Content
Introduction
 Main tasks in OpenTox
 Overview of the software developed by
Ideaconsult ltd.
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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
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Introduction
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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.
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Develops and maintains several well-known and widely used open
source software products, relevant to OpenTox, in particular
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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.
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Main Tasks in OpenTox:
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Work package 2 (Framework implementation)
leader
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Work package 3
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Building blocks for a (Q)SAR decision support system
(WP2)
Database for QSAR models (compliant with ECB QMRF)
(WP2)
AMBIT database with more than 450 000 chemical
compounds (WP3)
Work package 4
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Chemoinformatics and data mining algorithms (WP4)
Algorithms for the determination of chemical similarities
and applicability domains (WP4)
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Toxtree 1.51
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Estimates toxic hazard by
applying a decision tree
approach.
Full-featured and flexible userfriendly open source software
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Platform independent
Input:
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datasets from various compatible file
types
SMILES
built-in 2D structure diagram editor.
Output
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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
SDF, MOL, CSV, MS Excel, CML, TXT,
PDF, HTML
Batch mode
5 classification schemes (plugins) for various endpoints
assessment available
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Toxtree 1.51 plug-ins:
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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 corrosion
potential, 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”;
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A decision tree for estimating eye irritation and corrosion
potential, 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”;
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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.
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Toxtree internals
Series 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
Q19.Open chain
Yes
Q20.Aliphatic with some functional groups
Q21.3 or more different functional groups
Q18.One of the list (see explanation) No
Yes
No
Low (Class I)
Q30.Aromatic Ring with complex substituents
Q18.One of the list (see explanation) No
No
Low (Class I)
10-12 Sep 2008
OpenTox kick-off meeting
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Query compound
Hydrolysis
products
More on Toxtree
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Structure alerts defined by
SMARTS patterns
Descriptors calculation
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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
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Toxmatch 1.05
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Provides means to compare a
chemical or set of chemicals to a
toxicity dataset through the use
of similarity indices
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Includes datasets for four toxicity
endpoints to facilitate endpoint
specific read-across
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Intended use is one to many or many to
many quantitative read-across
To help in the systematic formation of
groups and 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
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Toxmatch 1.05 - methods
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Structure representations
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Similarity indices (pair wise)
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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
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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
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Descriptors
Fingerprints
Atom environments
EHOMO, ELUMO, Log P, MW can be
calculated
Verhaar and BfR skin irritation
schemes as available in Toxtree are
included
10-12 Sep 2008
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
Toxmatch 1.05 - methods
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Toxmatch is a promising tool to help in the
systematic formation of groups and readacross
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
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
AMBIT
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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:
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Ambit Database tools 1.30
(on the right)
Ambit Discovery (applicability
domain assessment)
Ambit Online
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
AMBIT Discovery
Software for applicability domain assessment
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Methods:
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More options
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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
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)
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
AMBIT Extensions
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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
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
AMBIT XT
Built upon AMBIT software
 Objectives:
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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
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10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
AMBIT XT emphasize on
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Data provenance
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Data quality
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Easy way for comparison between
different sources
Flexible storage for measured
data for different endpoints
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history of the updates of the
chemicals information.
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 plugin support)
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland
Thank you!
10-12 Sep 2008
OpenTox kick-off meeting
Basel, Switzerland