title: The application of molecular modelling in the safety assessment of chemicals: A case study on ligand-dependent PPARγ dysregulation.
abstract: The aim of this paper was to provide a proof of concept demonstrating that molecular modelling methodologies can be employed as a part of an integrated strategy to support toxicity prediction consistent with the mode of action/adverse outcome pathway (MoA/AOP) framework. To illustrate the role of molecular modelling in predictive toxicology, a case study was undertaken in which molecular modelling methodologies were employed to predict the activation of the peroxisome proliferator-activated nuclear receptor γ (PPARγ) as a potential molecular initiating event (MIE) for liver steatosis. A stepwise procedure combining different in silico approaches (virtual screening based on docking and pharmacophore filtering, and molecular field analysis) was developed to screen for PPARγ full agonists and to predict their transactivation activity (EC50). The performance metrics of the classification model to predict PPARγ full agonists were balanced accuracy=81%, sensitivity=85% and specificity=76%. The 3D QSAR model developed to predict EC50of PPARγ full agonists had the following statistical parameters: q2cv=0.610, Nopt=7, SEPcv=0.505, r2pr=0.552. To support the linkage of PPARγ agonism predictions to prosteatotic potential, molecular modelling was combined with independently performed mechanistic mining of available in vivo toxicity data followed by ToxPrint chemotypes analysis. The approaches investigated demonstrated a potential to predict the MIE, to facilitate the process of MoA/AOP elaboration, to increase the scientific confidence in AOP, and to become a basis for 3D chemotype development.
authors.affiliation: Institute of Biophysics and Biomedical Engineering-Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 105, 1113 Sofia, Bulgaria.
authors.forename: Merilin
authors.initials: M
authors.lastname: Al Sharif
authors.affiliation: Institute of Biophysics and Biomedical Engineering-Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 105, 1113 Sofia, Bulgaria. Electronic address: ITsakovska@biomed.bas.bg.
authors.forename: Ivanka
authors.initials: I
authors.lastname: Tsakovska
authors.affiliation: Institute of Biophysics and Biomedical Engineering-Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 105, 1113 Sofia, Bulgaria.
authors.forename: Ilza
authors.initials: I
authors.lastname: Pajeva
authors.affiliation: Institute of Biophysics and Biomedical Engineering-Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 105, 1113 Sofia, Bulgaria.
authors.forename: Petko
authors.initials: P
authors.lastname: Alov
authors.affiliation: S-IN Soluzioni Informatiche SRL, Via Ferrari 14, Vicenza 36100, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Fioravanzo
authors.affiliation: S-IN Soluzioni Informatiche SRL, Via Ferrari 14, Vicenza 36100, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bassan
authors.affiliation: S-IN Soluzioni Informatiche SRL, Via Ferrari 14, Vicenza 36100, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Kovarich
authors.affiliation: Altamira LLC, 1455 Candlewood Drive, Columbus, OH 43235, USA.
authors.forename: Chihae
authors.initials: C
authors.lastname: Yang
authors.affiliation: Altamira LLC, 1455 Candlewood Drive, Columbus, OH 43235, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mostrag-Szlichtyng
authors.affiliation: Altamira LLC, 1455 Candlewood Drive, Columbus, OH 43235, USA; Faculty of Pharmacy, Medical University of Sofia, "Dunav" 2 str., Sofia, Bulgaria.
authors.forename: Vessela
authors.initials: V
authors.lastname: Vitcheva
authors.affiliation: Systems Toxicology Unit, Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra, Varese, Italy.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Worth
authors.affiliation: School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, England.
authors.forename: Andrea-N
authors.initials: AN
authors.lastname: Richarz
authors.affiliation: School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, England.
authors.forename: Mark T D
authors.initials: MTD
authors.lastname: Cronin
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D030562:Databases, Protein; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005240:Feasibility Studies; D057809:HEK293 Cells; D000882:Haplorhini; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D008024:Ligands; D047495:PPAR gamma
keywords: Adverse outcome pathway; Liver steatosis; Molecular modelling; PPARγ; Receptor activation