title: Integrative Modeling Strategies for Predicting Drug Toxicities at the eTOX Project.
abstract: Early prediction of safety issues in drug development is at the same time highly desirable and highly challenging. Recent advances emphasize the importance of understanding the whole chain of causal events leading to observable toxic outcomes. Here we describe an integrative modeling strategy based on these ideas that guided the design of eTOXsys, the prediction system used by the eTOX project. Essentially, eTOXsys consists of a central server that marshals requests to a collection of independent prediction models and offers a single user interface to the whole system. Every of such model lives in a self-contained virtual machine easy to maintain and install. All models produce toxicity-relevant predictions on their own but the results of some can be further integrated and upgrade its scale, yielding in vivo toxicity predictions. Technical aspects related with model implementation, maintenance and documentation are also discussed here. Finally, the kind of models currently implemented in eTOXsys is illustrated presenting three example models making use of diverse methodology (3D-QSAR and decision trees, Molecular Dynamics simulations and Linear Interaction Energy theory, and fingerprint-based QSAR).
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, E-08003 Barcelona, Spain phone/fax: +34933160512; +34933160550.
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, E-08003 Barcelona, Spain phone/fax: +34933160512; +34933160550.
authors.forename: Pau
authors.initials: P
authors.lastname: Carrió
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, E-08003 Barcelona, Spain phone/fax: +34933160512; +34933160550.
authors.forename: Oriol
authors.initials: O
authors.lastname: López
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Luigi
authors.initials: L
authors.lastname: Capoferri
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Derk P
authors.initials: DP
authors.lastname: Kooi
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Daan P
authors.initials: DP
authors.lastname: Geerke
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Floriane
authors.initials: F
authors.lastname: Montanari
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.affiliation: Molecular Networks GmbH, Medical Valley Center, Henkestrasse 91, Erlangen 91052, Germany.
authors.forename: Christof H
authors.initials: CH
authors.lastname: Schwab
authors.affiliation: Molecular Networks GmbH, Medical Valley Center, Henkestrasse 91, Erlangen 91052, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kleinöder
authors.affiliation: Molecular Networks GmbH, Medical Valley Center, Henkestrasse 91, Erlangen 91052, Germany.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Magdziarz
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, E-08003 Barcelona, Spain phone/fax: +34933160512; +34933160550. manuel.pastor@upf.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
mesh_terms: D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008954:Models, Biological; D056004:Molecular Dynamics Simulation
keywords: AOP; Drug safety; Integrative modeling; Multi-scale models; Toxicity prediction