Hazard identification of cis/trans -zearalenone through the looking-glass

Dellafiora, Luca; Galaverna, Gianni; Dall’Asta, Chiara; Cozzini, Pietro

doi:10.1016/j.fct.2015.09.009

Cited by 25 publications

(16 citation statements)

References 39 publications

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“…Pharmacophoric modeling of the CK2 binding site was performed using the Flapsite tool of the FLAP software (www.moldi scove ry.com), while the GRID algorithm was used to investigate the corresponding pharmacophoric space (Baroni et al 2007;Carosati et al 2004). Docking simulations were done using the software GOLD (Genetic Optimization for Ligand Docking), as it previously succeeded in providing reliable architectures of binding and in predicting the activity of compounds of toxicological concern (e.g., Dellafiora et al 2015;Maldonado-Rojas et al 2011). Specifically, the model of the catalytic domain of human CK2 derives from the crystallographic structure having PDB code 3OWL (Prudent et al 2010).…”

Section: Structure-based Molecular Modelingmentioning

confidence: 99%

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

et al. 2020

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Emerging mycotoxins produced by Alternaria spp. were previously reported to exert cytotoxic, genotoxic, but also estrogenic effects in human cells. The involved mechanisms are very complex and not fully elucidated yet. Thus, we followed an in silico target fishing approach to extend knowledge on the possible biological targets underlying the activity of alternariol, taken as the signature compound of Alternaria toxins. Combining ligand-based screening and structure-based modeling, the ubiquitous casein kinase 2 (CK2) was identified as a potential target for the compound. This result was validated in a cellfree in vitro CK2 activity assay, where alternariol inhibited CK2 with an IC 50 of 707 nM. As CK2 was recently discussed to influence estrogen receptor (ER) transcription and DNA-binding affinity, we assessed a potential impact on the mRNA levels of ERα or ERβ by qRT-PCR and on nuclear localization of the receptors by confocal microscopy, using estrogen-sensitive Ishikawa cells as a model. While AOH did not affect the transcription of ERα or ERβ, an increase in nuclear localization of ERα after incubation with 10 µM AOH was observed. However, this effect might be due to ER binding affinity and therefore estrogenicity of AOH. Furthermore, in silico docking simulation revealed not only AOH, but also a number of other Alternaria toxins as potential inhibitors of CK2, including alternariol monomethyl ether and the perylene quinone derivative altertoxin II (ATX-II). These findings were representatively confirmed in vitro for the perylene quinone derivative altertoxin II, which was found to inhibit the kinase with an IC 50 of 5.1 µM. Taken together, we propose CK2 inhibition as an additional mechanism to consider in future studies for alternariol and several other Alternaria toxins.

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Section: Structure-based Molecular Modelingmentioning

confidence: 99%

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

et al. 2020

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“…The capability of each mutation to affect the InlA-Ecad surface interaction was assessed and compared to the wt complex computing the overall interaction score of each complex with the HINT scoring function [26]. In particular, HINT score has an inverse relationship to the free energy of binding (the higher the score, the stronger the interaction expected) [34] and it previously proved reliable to compute protein-macromolecule complex formation (including protein-protein and protein-DNA complex) [22,35].…”

Section: Assessment Of Interface Interactionmentioning

confidence: 99%

A Structural Study on the Listeria Monocytogenes Internalin A—Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations

Dellafiora

Filipello

Dall’Asta

et al. 2020

Toxins

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Listeria monocytogenes is a widespread foodborne pathogen of high concern and internalin A is an important virulence factor that mediates cell invasion upon the interaction with the host protein E-cadherin. Nonsense mutations of internalin A are known to reduce virulence. Although missense mutations are largely overlooked, they need to be investigated in respect to their effects in cell invasion processes. This work presented a computational workflow to early characterize internalin A missense mutations. The method reliably estimated the effects of a set of engineered missense mutations in terms of their effects on internalin A–E-cadherin interaction. Then, the effects of mutations of an internalin A variant from a L. monocytogenes isolate were calculated. Mutations showed impairing effects on complex stability providing a mechanistic explanation of the low cells invasion capacity previously observed. Overall, our results provided a rational approach to explain the effects of internalin A missense mutations. Moreover, our findings highlighted that the strength of interaction may not directly relate to the cell invasion capacity reflecting the non-exclusive role of internalin A in determining the virulence of L. monocytogenes. The workflow could be extended to other virulence factors providing a promising platform to support a better molecular understanding of L. monocytogenes epidemiology.

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“…This approach was further exploited to predict and rank ZEN metabolites towards ER for hazard characterization [43,44]. The investigation of receptor-ligand interactions through docking simulation proved to accurately rank estrogenic potencies of ZEN and its metabolites, showing the suitability of the model to address estrogenic potency for this group of compounds [43,44].…”

Section: Mycotoxin and Nuclear Receptorsmentioning

confidence: 99%

Mycotoxins and Nuclear Receptors: A Still Underexplored Issue

Dall’Asta¹

2016

Nuclear Receptor Research

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Abstract.Mycotoxins are fungal secondary metabolites that can be found in food commodities worldwide. They exert a wide range of adverse effects towards humans and animals. Although toxicological studies have addressed these food contaminants over decades, their mode of actions as well as their synergistic effects are still to be deeply clarified. Among the toxicological targets, nuclear receptors have been identified by several studies. Besides the estrogenic effect, a wider range of endocrine and neuroendocrine disrupting effects have been reported so far. This review is aimed at addressing the recent advances in toxicology, and at highlighting possible gaps of knowledge.

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Hazard identification of cis/trans -zearalenone through the looking-glass

Cited by 25 publications

References 39 publications

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

A Structural Study on the Listeria Monocytogenes Internalin A—Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations

Mycotoxins and Nuclear Receptors: A Still Underexplored Issue

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