The COSMOS KNIME WebPortal Making COSMOS In Silico Models ...€¦ · 1 KNIME.com AG, Zurich,...
1
Query compounds can be profiled using structural alerts, based on organic reaction mechanisms, and chemotypes. Currently available: • 108 alerts for covalent binding to proteins (MIE for endpoints such as hepatotoxicity) • 85 for DNA binding • 32 for phospholipidosis and 16 for other liver toxicity • 30 for mitochondrial toxicity. • KNIME workflows implementing QSAR classification models for the prediction of LXR binding potential are available and can be run through the KNIME WebPortal. Thorsten Meinl 1 , Alicia Paini 2 , Anna Palczewska 3 , Fabian Steinmetz 4 , Simona Kovarich 5 , Jose Vicente Sala Benito 2 , Petko Alov 6 , Andrea-Nicole Richarz 4 The COSMOS KNIME WebPortal – Making COSMOS In Silico Models Available 1 KNIME.com AG, Zurich, Switzerland, 2 European Commission – Joint Research Centre, IHCP, Ispra, Italy, 3 University of Bradford, England, 4 School of Pharmacy and Chemistry, Liverpool John Moores University, England, 5 S-IN Soluzioni Informatiche SRL, Vicenza, Italy, 6 Institute of Biophysics and Biomedical Engineering, Bulg. Academy of Sciences, Sofia, Bulgaria [email protected] The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) COSMOS Project under grant agreement n°266835 and from Cosmetics Europe. Acknowledgements www.cosmostox.eu • The KNIME Analytics Platform (http://www.knime.org) allows to easily create graphical workflows for processing all kinds of data • Workflows are very flexible and can be configured variably • The KNIME WebPortal allows non-experienced users to execute workflows in a browser • No local installation required • Easy selection of available workflows • Wizard-like execution where only selected configuration options are requested • Results are provided as downloadable files (e.g. Excel sheets), PDF reports, or images • WebPortal workflows are uploaded by power users from the local client application • COSMOS KNIME WebPortal is available at http://knimewebportal.cosmostox.eu • Login can be requested via COSMOS Space http://cosmosspace.cosmostox.eu COSMOS KNIME WebPortal • A KNIME workflow was developed that searches the structure of a chemical for a particular structural rule, associated with a mechanism of action, and identifies compounds with the same rules from a list of compounds to form a category and subcategories. Structural Alerts and Models • Cosmetics are usually applied dermally, while the majority of available repeated dose toxicity data are obtained from oral administration experiments. • To facilitate extrapolation between oral and dermal administrations for repeated dose toxicity, two in silico models predicting: skin permeability (SP) Absorption have been developed and implemented as KNIME workflows. gastrointestinal absorption (GIA) Biokinetics In order to help the Risk Assessment process a series of KNIME workflows were developed to perform simulation and extrapolation in an automated way : • Biokinetic simulations, route to route (RtoR) extrapolation and human bioaccumulation factor (hBCF), can be performed by applying Physiologically Based Kinetic (PBK) models (see Figure 1). • Several workflows for In Vitro to In Vivo Extrapolation (IVIVE) have been developed. Coupling in vitro dynamics with PBK models we can relate an exposure dose to an intracellular concentration to a dynamic effect that can be used to extrapolate in vitro to in vivo organ-toxicity (see Figure 2). • The in vitro intracellular concentrations can be extra- polated by applying the Virtual Cell Assay (VCA, see Figure 3). Figure 1. PBK model KNIME workflow Figure 2. IVIVE model KNIME workflow Figure 3. VCA KNIME workflow • Chemical space analysis of datasets as a preliminary step before modelling. It includes Principal Component Analysis (PCA) and distribution analysis (based on various descriptors), and functional groups profiling. • A workflow based on PaDEL descriptors is available through the KNIME WebPortal. Chemical Space Analysis Frequency (%) of functional groups within each class PCA (Biplot)
Transcript of The COSMOS KNIME WebPortal Making COSMOS In Silico Models ...€¦ · 1 KNIME.com AG, Zurich,...
Query compounds can be profiled using structural alerts, based on organic reaction mechanisms, and chemotypes. Currently available:
• 108 alerts for covalent binding to proteins (MIE for endpoints such as hepatotoxicity)
• 85 for DNA binding
• 32 for phospholipidosis and 16 for other liver toxicity
• 30 for mitochondrial toxicity.
• KNIME workflows implementing QSAR classification models for the prediction of LXR binding potential are available and can be run through the KNIME WebPortal.
Thorsten Meinl1, Alicia Paini2, Anna Palczewska3, Fabian Steinmetz4, Simona Kovarich5, Jose Vicente Sala Benito2, Petko Alov6, Andrea-Nicole Richarz4
The COSMOS KNIME WebPortal – Making COSMOS In Silico Models Available
1 KNIME.com AG, Zurich, Switzerland, 2 European Commission – Joint Research Centre, IHCP, Ispra, Italy, 3 University of Bradford, England, 4 School of Pharmacy and Chemistry, Liverpool John Moores University, England, 5 S-IN Soluzioni Informatiche SRL, Vicenza, Italy, 6 Institute of Biophysics and Biomedical Engineering, Bulg. Academy of Sciences, Sofia, Bulgaria [email protected]
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) COSMOS Project under grant agreement n°266835 and from Cosmetics Europe.
Acknowledgements www.cosmostox.eu
• The KNIME Analytics Platform (http://www.knime.org) allows to easily create graphical workflows for processing all kinds of data
• Workflows are very flexible and can be configured variably
• The KNIME WebPortal allows non-experienced users to execute workflows in a browser
• No local installation required
• Easy selection of available workflows
• Wizard-like execution where only selected configuration options are requested
• Results are provided as downloadable files (e.g. Excel sheets), PDF reports, or images
• WebPortal workflows are uploaded by power users from the local client application
• COSMOS KNIME WebPortal is available at http://knimewebportal.cosmostox.eu
• Login can be requested via COSMOS Space http://cosmosspace.cosmostox.eu
COSMOS KNIME WebPortal
• A KNIME workflow was developed that searches the structure of a chemical for a particular structural rule, associated with a mechanism of action, and identifies compounds with the same rules from a list of compounds to form a category and subcategories.
Structural Alerts and Models
• Cosmetics are usually applied dermally, while the majority of available repeated dose toxicity data are obtained from oral administration experiments.
• To facilitate extrapolation between oral and dermal administrations for repeated dose toxicity, two in silico models predicting:
skin permeability (SP)
Absorption
have been developed and implemented as KNIME workflows.
gastrointestinal absorption (GIA)
Biokinetics In order to help the Risk Assessment process a series of KNIME workflows were developed to perform simulation and extrapolation in an automated way :
• Biokinetic simulations, route to route (RtoR) extrapolation and human bioaccumulation factor (hBCF), can be performed by applying Physiologically Based Kinetic (PBK) models (see Figure 1).
• Several workflows for In Vitro to In Vivo Extrapolation (IVIVE) have been developed. Coupling in vitro dynamics with PBK models we can relate an exposure dose to an intracellular concentration to a dynamic effect that can be used to extrapolate in vitro to in vivo organ-toxicity (see Figure 2).
• The in vitro intracellular concentrations can be extra-polated by applying the Virtual Cell Assay (VCA, see Figure 3).
Figure 1. PBK model KNIME workflow
Figure 2. IVIVE model KNIME workflow
Figure 3. VCA KNIME workflow
• Chemical space analysis of datasets as a preliminary step before modelling. It includes Principal Component Analysis (PCA) and distribution analysis (based on various descriptors), and functional groups profiling.
• A workflow based on PaDEL descriptors is available through the KNIME WebPortal.
Chemical Space Analysis
Frequency (%) of functional groups within each class
PCA (Biplot)
