Molecular Modeling to predict the ligand binding key event

Modern Molecular Modeling methods are at the core of mechanistic and computational toxicology, indeed these methods are able to analyze 3D molecular structures and their interactions in order to better understand the mechanism by which toxic compounds or drugs execute their action. Toxic effects of a molecule can be explained by the Adverse Outcome Pathway model (AOP); the molecular initiating event (MIE) can be the interaction of the molecule with a biological target, a protein for example. After the initial interaction many Key Events can link the MIE to the Adverse Outcome. It is useful to describe also the Key Event Relationship to assess the causal nature between two measurable biological events. Our focus of study is the Aryl hydrocarbon Receptor (AhR), a ligand-dependent transcription factor that responds to exogenous and endogenous chemicals with the induction of gene expression and production of diverse biological and toxic effects. Well known ligands of AhR are polychlorinated-dibenzodioxins (among them the 2,3,7,8-TCDD), dibenzofurans and biphenyls (PCB), and polycyclic aromatic hydrocarbons (PAH). The analysis of specific binding interactions of ligands within the AhR Ligand Binding Domain (LBD) would allow a deeper comprehension of the key molecular events regulating the mechanism of ligand-dependent and ligand-specific AhR activation. Aim of our current studies is to combine molecular modeling methods with experimental approaches to gain insights into the binding specificity of AhR ligands with different structures and properties