Showing papers by "Ivanka Tsakovska published in 2014"

Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

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.

Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPAR γ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease.

Abstract: Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP) of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD) are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE) for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPARγ activation in hepatocytes and (ii) PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

Molecular Dynamics Simulation of the Human Estrogen Receptor Alpha: Contribution to the Pharmacophore of the Agonists

Abstract: Human estrogen receptor alfa (ER alfa) is one of the most studied targets for in silico sc reening of bioactive compounds. The estrogenic activity of a vast number of chemicals has been studied for their potentially adverse effects on the hormone regulation of the endocrine system. The commonly accepted presentation of the ER alfa agonist pharmacophore includes terminal phenolic groups and a hydrophobic core with a rigid framework. In this study we report on molecular dynamic (MD) simulations of ER alfa to get a deeper structural insight into the agonist-receptor interactions and the pharmacophore pattern of compounds with agonistic activity. We rely on a crystallographic structure of a complex of ER alfa with an agonist of picomolar affinity . As the X-ray structure has mutation in the key structural element for ER alfa agonistic activity (helix 12, Y537S), a series of MD simulations have been performed on the wild type receptor to prove the stability of the agonist-receptor interactions. The results suggest that the pharmacophore of compounds with ER alfa a gonistic activity can be extended by a feature that occupies a free hydrophobic region of the binding pocket. The results imply also that MD simulations are a powerful in silico tool for both protein dynamics and structure investigation, especially when mutations are available that can potentially disturb the protein structure and functions.