Molecular Modelling Study of the PPAR[gamma] Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

• Published in: International journal of molecular sciences Vol. 15; no. 5; p. 7651
• Main Authors: Tsakovska, Ivanka, Sharif, Merilin Al, Alov, Petko, Diukendjieva, Antonia, Fioravanzo, Elena, Cronin, Mark T D, Pajeva, Ilza
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.05.2014
• Subjects: Liver diseases; Mathematical models; Molecular biology; Proteins
• ISSN: 1661-6596; 1422-0067
• DOI: 10.3390/ijms15057651

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 PPAR[gamma] ligand-dependent activation as a key MIE in the elicitation of liver steatosis. Synthetic PPAR[gamma] 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 PPAR[gamma] 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 PPAR[gamma] activation. The results are useful for the characterisation of the chemical space of PPAR[gamma] full agonists and could facilitate the development of preliminary filtering rules for the effective virtual ligand screening of compounds with PPAR[gamma] full agonistic activity.