title: 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.
authors.affiliation: Institute of Biophysics and Biomedical Engineering-BAS, Acad. G. Bonchev Str., Bl.105, Sofia 1113, Bulgaria. ITsakovska@biomed.bas.bg.
authors.forename: Ivanka
authors.initials: I
authors.lastname: Tsakovska
authors.affiliation: Institute of Biophysics and Biomedical Engineering-BAS, Acad. G. Bonchev Str., Bl.105, Sofia 1113, Bulgaria. merilin.al@biomed.bas.bg.
authors.forename: Merilin
authors.initials: M
authors.lastname: Al Sharif
authors.affiliation: Institute of Biophysics and Biomedical Engineering-BAS, Acad. G. Bonchev Str., Bl.105, Sofia 1113, Bulgaria. petko@biophys.bas.bg.
authors.forename: Petko
authors.initials: P
authors.lastname: Alov
authors.affiliation: Institute of Biophysics and Biomedical Engineering-BAS, Acad. G. Bonchev Str., Bl.105, Sofia 1113, Bulgaria. antonia.diuk@gmail.com.
authors.forename: Antonia
authors.initials: A
authors.lastname: Diukendjieva
authors.affiliation: Soluzioni Informatiche srl, Via Ferrari 14, Vicenza 36100, Italy. elena.fioravanzo@s-in.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Fioravanzo
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK. M.T.Cronin@ljmu.ac.uk.
authors.forename: Mark T D
authors.initials: MT
authors.lastname: Cronin
authors.affiliation: Institute of Biophysics and Biomedical Engineering-BAS, Acad. G. Bonchev Str., Bl.105, Sofia 1113, Bulgaria. pajeva@biomed.bas.bg.
authors.forename: Ilza
authors.initials: I
authors.lastname: Pajeva
mesh_terms: D001665:Binding Sites; D030562:Databases, Protein; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D008024:Ligands; D047495:PPAR gamma; D020033:Protein Isoforms