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Int. J. Mol. Sci. 2014, 15(5), 7651-7666;

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

Institute of Biophysics and Biomedical Engineering—BAS, Acad. G. Bonchev Str., Bl.105, Sofia 1113, Bulgaria
Soluzioni Informatiche srl, Via Ferrari 14, Vicenza 36100, Italy
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK
Authors to whom correspondence should be addressed.
Received: 30 March 2014 / Revised: 18 April 2014 / Accepted: 21 April 2014 / Published: 5 May 2014
(This article belongs to the Collection Proteins and Protein-Ligand Interactions)
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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. View Full-Text
Keywords: PPARγ; liver steatosis; mode of action; molecular modelling; pharmacophore PPARγ; liver steatosis; mode of action; molecular modelling; pharmacophore

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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Tsakovska, I.; Al Sharif, M.; Alov, P.; Diukendjieva, A.; Fioravanzo, E.; Cronin, M.T.D.; Pajeva, I. Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis. Int. J. Mol. Sci. 2014, 15, 7651-7666.

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