A Systems Biology Approach for Identifying Hepatotoxicant Groups Based on Similarity in Mechanisms of Action and Chemical Structure.
When evaluating compound similarity, addressing multiple sources of information to reach conclusions about common pharmaceutical and/or toxicological mechanisms of action is a crucial strategy. In this chapter, we describe a systems biology approach that incorporates analyses of hepatotoxicant data for 33 compounds from three different sources: a chemical structure similarity analysis based on the 3D Tanimoto coefficient, a chemical structure-based protein target prediction analysis, and a cross-study/cross-platform meta-analysis of in vitro and in vivo human and rat transcriptomics data derived from public resources (i.e., the diXa data warehouse). Hierarchical clustering of the outcome scores of the separate analyses did not result in a satisfactory grouping of compounds considering their known toxic mechanism as described in literature. However, a combined analysis of multiple data types may hypothetically compensate for missing or unreliable information in any of the single data types. We therefore performed an integrated clustering analysis of all three data sets using the R-based tool iClusterPlus. This indeed improved the grouping results. The compound clusters that were formed by means of iClusterPlus represent groups that show similar gene expression while simultaneously integrating a similarity in structure and protein targets, which corresponds much better with the known mechanism of action of these toxicants. Using an integrative systems biology approach may thus overcome the limitations of the separate analyses when grouping liver toxicants sharing a similar mechanism of toxicity.
Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute, Maastricht University, Universiteitssingel 40, Maastricht, 6229ER, The Netherlands. d.hebels@maastrichtuniversity.nl.|Department of Toxicogenomics, Maastricht University, Universiteitssingel 40, Maastricht, 6229ER, The Netherlands. d.hebels@maastrichtuniversity.nl.
Dennie G A J
DG
Hebels
Department of Computational Molecular Biology, Bioinformatics Group, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin, 14195, Germany.
Axel
A
Rasche
Department of Computational Molecular Biology, Bioinformatics Group, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin, 14195, Germany.
Ralf
R
Herwig
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, 2300 RA, The Netherlands.
Gerard J P
GJ
van Westen
Department of Toxicogenomics, Maastricht University, Universiteitssingel 40, Maastricht, 6229ER, The Netherlands.
Danyel G J
DG
Jennen
Department of Toxicogenomics, Maastricht University, Universiteitssingel 40, Maastricht, 6229ER, The Netherlands.
Jos C S
JC
Kleinjans
D000818:Animals; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000187:drug effects*; D015394:Molecular Structure; D051381:Rats; D012984:Software; D049490:Systems Biology / Q000379:methods*; D018675:Toxicity Tests / Q000379:methods*; D043922:Toxicogenetics
3D Tanimoto; Chemical structure; Hepatotoxicity; Mechanism of action; Meta-analysis; Protein targets; Similarity; Systems biology; diXa; iClusterPlus