title: Molecular modelling approach to evaluate poisoning of topoisomerase I by alternariol derivatives.
abstract: Alternaria species are widespread microfungi the secondary metabolites of which may accumulate in crops and enter into food production chain. Among them, the "emerging mycotoxin" alternariol and alternariol-methyl ether arouse concern due to evidences of toxicity. In particular, the disruption of topoisomerases leads to genotoxic outcomes. Metabolic modifications may drastically reduce toxic potency by enhancing clearance and/or by preventing interaction with the pharmacological targets. However, the metabolic activation may occur as well. For this reason, understanding the role of metabolised forms is paramount for the in-depth comprehension of adverse effects on living organisms, thus providing a more informed scenario for risk assessment. Regardless that a wealth of alternariol metabolites and derivatives has been identified, most have not been tested with respect to topoisomerases. Consequently, their effects in living organism are not yet well understood. Unfortunately, experimental analysis is challenging and time-consuming. With the aim of analysing a wide array of alternariol metabolites and derivatives, we presented an effective framework based on a straightforward in silico procedure. Interestingly, several metabolites were predicted to be poisons, strongly suggesting the need for further experimental trials and their inclusion in future risk assessment studies.
authors.affiliation: Molecular Modeling Laboratory, Department of Food Science, University of Parma, Parco Area delle Scienze 95/A, 43125 Parma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Dellafiora
authors.affiliation: Department of Food Science, University of Parma, Parco Area delle Scienze 95/A, 43125 Parma, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dall'Asta
authors.affiliation: Laboratory for Chemometrics and Cheminformatics, Chemistry Department, University of Perugia, Via Elce di Sotto 8, I-06123 Perugia, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.affiliation: Department of Food Science, University of Parma, Parco Area delle Scienze 95/A, 43125 Parma, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Galaverna
authors.affiliation: Molecular Modeling Laboratory, Department of Food Science, University of Parma, Parco Area delle Scienze 95/A, 43125 Parma, Italy. Electronic address: pietro.cozzini@unipr.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
mesh_terms: D000528:Alternaria / Q000737:chemistry*; D019295:Computational Biology; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D007783:Lactones / Q000737:chemistry*; D008958:Models, Molecular; D009183:Mycotoxins / Q000737:chemistry; D015203:Reproducibility of Results; D059004:Topoisomerase I Inhibitors / Q000737:chemistry*
chemical_list: D007783:Lactones; D009183:Mycotoxins; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C005197:alternariol
keywords: Alternaria metabolites; Alternariol; In silico prediction; Molecular modelling; Poisoning; Topoisomerase I