Molecular modelling approach to evaluate poisoning of topoisomerase I by alternariol derivatives

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" altemariol and altemariol-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 altemariol 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. (C) 2015 Elsevier Ltd. All rights reserved.