Abstract
The comprehensive understanding of the precise mode of action and/or adverse outcome pathway (MoA/AOP) of chemicals has become a key step toward the development of a new generation of predictive toxicology tools. One of the challenges of this process is to test the feasibility of the molecular modelling approaches to explore key molecular initiating events (MIE) within the integrated strategy of MoA/AOP characterisation. The description of MoAs leading to toxicity and liver damage has been the focus of much interest. Growing evidence underlines liver PPARγ ligand-dependent activation as a key MIE in the elicitation of liver steatosis. Synthetic PPARγ full agonists are of special concern, since they may trigger a number of adverse effects not observed with partial agonists. In this study, molecular modelling was performed based on the PPARγ complexes with full agonists extracted from the Protein Data Bank. The receptor binding pocket was analysed, and the specific ligand-receptor interactions were identified for the most active ligands. A pharmacophore model was derived, and the most important pharmacophore features were outlined and characterised in relation to their specific role for PPARγ activation. The results are useful for the characterisation of the chemical space of PPARγ full agonists and could facilitate the development of preliminary filtering rules for the effective virtual ligand screening of compounds with PPARγ full agonistic activity.
Highlights
IntroductionModern toxicology concepts aim at building alternative models (in vitro and in silico) to predict the adverse effects of chemicals
Modern toxicology concepts aim at building alternative models to predict the adverse effects of chemicals
Within the mode of action and/or adverse outcome pathway (MoA/adverse outcome pathway (AOP)) framework, the description and characterisation of the toxicological mode of action (MoA) leading to liver toxicity are of specific interest, since the liver is a major organ affected by toxicity
Summary
Modern toxicology concepts aim at building alternative models (in vitro and in silico) to predict the adverse effects of chemicals This requires comprehensive understanding of biological pathways starting at the molecular level and their relationship to adverse effects at the organ and higher levels of organism organization [1]. PPARγ has two isoforms, PPARγ1 and PPARγ2, the latter possessing an additional thirty amino acids in the N-terminal part It has an overall domain structure typical for nuclear hormone receptors comprised of: an N-terminal AF-1 (transactivation function 1) domain that participates in the interaction with cofactors and is responsible for ligand-independent transactivation; a DBD (DNA binding domain) that is highly conserved among nuclear receptors; a highly flexible hinge region, necessary for nuclear localisation and cofactor docking; and a C-terminal LBD/AF-2 (ligand binding domain/activation function 2) that participates in ligand-binding, ligand-dependent transactivation, coactivator recruitment and corepressor release (Figure 1). The pharmacophore features were evaluated according to their role in PPARγ interactions and the transactivation activity of the full agonists
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