95 research outputs found
In silico approach to evaluate molecular interaction between mycotoxins and the estrogen receptors ligand binding domain: A case study on zearalenone and its metabolites.
No full textAn association of virtual screening, docking and a good rescoring procedure is a well known technique to discover and design new lead compounds in medicinal chemistry. We have demonstrated that the study on the interactions of unsuspected molecules with estrogen receptors, using the same technique applied in medicinal chemistry could be a valuable choice to discover new hypothetical xenoestrogens. The same approach can be applied to a wide set of chemicals found in food and seed. We propose this approach using as a case study on the zearalenone family to food safety. Zearalenone and its reductive metabolites are a well known set of mycotoxins able to bind estrogen receptors (ERs) thereby interfering with the endogenous estrogenic response. Their endocrine disrupting behavior is tightly related to their capability to competitively bind the ligand binding pocket (LBP) and to stabilize at least one of the functionally active conformational assets of the ligand binding domain (LBD). Although proposing an interacting model alongside for three-dimensional complexes is not yet solved, this kind of computational aided analysis is a potentially intriguing tool to predict the binding event and to evaluate the xenoestrogenic role of any kind of chemicals and derivatives
Degradation of Aflatoxins by Means of Laccases from Trametes versicolor: An In Silico Insight
No full textMycotoxins are secondary metabolites of fungi that contaminate food and feed, and are involved in a series of foodborne illnesses and disorders in humans and animals. The mitigation of mycotoxin content via enzymatic degradation is a strategy to ensure safer food and feed, and to address the forthcoming issues in view of the global trade and sustainability. Nevertheless, the search for active enzymes is still challenging and time-consuming. The in silico analysis may strongly support the research by providing the evidence-based hierarchization of enzymes for a rational design of more effective experimental trials. The present work dealt with the degradation of aflatoxin B1 and M1 by laccase enzymes from Trametes versicolor. The enzymes–substrate interaction for various enzyme isoforms was investigated through 3D molecular modeling techniques. Structural differences among the isoforms have been pinpointed, which may cause different patterns of interaction between aflatoxin B1 and M1. The possible formation of different products of degradation can be argued accordingly. Moreover, the laccase gamma isoform was identified as the most suitable for protein engineering aimed at ameliorating the substrate specificity. Overall, 3D modeling proved to be an effective analytical tool to assess the enzyme–substrate interaction and provided a solid foothold for supporting the search of degrading enzyme at the early stage
IN SILICO EVALUATION OF SILVESTROL, ROCAGLAMIDE AND OTHER FLAVAGLINE COMPOUNDS AS POSSIBLE HEPATITIS E VIRUS INHIBITORS
No full textHepatitis E Virus (HEV) is a small positive sense single stranded RNA virus member of the Hepiviridae family,
particularly of the Orthohepevirus genus. It leads to 20 million HEV estimated infections/year worldwide and 3.3
million symptomatic cases of Hepatitis E, according to the World Health Organization [1]. While the fatality rate
usually ranges from 0.2% to 4%, it significantly increases for pregnant women [2]. The virus spreads via waterborne,
zoonotic and foodborne transmission depending both on the considered country and on the considered HEV genotype
[3, 4]. Pigs are the main reservoirs but even game and livestock, with all the related meat-based products, are a major
source of infection [5-9].
Unfortunately, HEV in vitro culture and analysis are still difficult, resulting in a poor understanding of its
molecular biology [10]. Moreover, HEV encodes for only one non-structural protein (ORF1): a multifunctional,
multidomain, non-cleaved polyprotein which could be a potential druggable target but whose crystallization results
unfeasible due to size-related reasons (185 kDa) [11].
In this context, an in-silico approach succeeded at overcoming the lack of HEV ORF1 structural data, allowing the
identification of potential anti-viral compounds. Based on previous studies showing the inhibitory activity of the
natural plant secondary metabolite silvestrol against HEV [12], our study provided a reliable model to: I) investigate
the underpinning mechanisms; and II) provide a predictive framework to estimate the activity of silvestrol analogues
for further dedicated investigations. The HEV RNA Helicase domain was modelled and refined via a homology
modelling approach based on an innovative, crystallome-based strategy. Then the interaction with 9 silvestrol-related
compounds, including rocaglamide and silvestrol, and 2 virtual decoys recovered from the DUD-E database, was
computed via docking and molecular dynamics simulations.
Overall, our study presented mechanistic insights on HEV RNA Helicases and silvestrol dependent inhibition,
expanded the current understanding of the structure-activity relationship for Silvestrol-related compounds and
provided a blueprint for further analysis targeting the HEV RNA Helicase. Eventually, in-depth investigation is warmly
sought to possibly extend the usage of either silvestrol, rocaglamide or some of the related natural compounds as feed
additives in order to reduce the HEV diffusion in livestock. Notably, silvestrol has already been proven to be well
tolerated in animals [13]
Ergot alkaloids: From witchcraft till in silico analysis. Multi-receptor analysis of ergotamine metabolites
No full textAbstractThe term Ergot is referred to the sclerotium of ascomycetes – a protective kernel produced during resting stage of some fungi – which replaces seeds of susceptible cereals and plants intended for human and animal diet. It contains various composition of tryptophan-derived toxins defined ergot alkaloids. Since sclerotia can be harvested and milled together with cereals, they represent a source of food and feed contamination after breakage and spreading of mycotoxins into the various milling fractions. The effects of ergot alkaloids, including those adverse for human health, have been known since the Middle Ages. Nevertheless, as recently stated by the European Food Safety Authority, further information is needed on metabolism and target receptors-binding of common alkaloids in food. Unfortunately, the experimental investigation is challenging due to the high costs in terms of time and money. This study was thus aimed at assessing whether the in silico modeling can be an effective tool to investigate the interaction between multiple serotonin receptors and a wide set of ergotamine metabolites, including experimentally detected molecules and predicted derivatives. Validated models provided precious insights about the effects exerted by metabolic modifications on the receptor–ligand interaction. Such structural information may be useful to support the design of further experimental analysis
Toxicodynamics of Mycotoxins in the Framework of Food Risk Assessment—An In Silico Perspective
No full textMycotoxins severely threaten the health of humans and animals. For this reason, many countries have enforced regulations and recommendations to reduce the dietary exposure. However, even though regulatory actions must be based on solid scientific knowledge, many aspects of their toxicological activity are still poorly understood. In particular, deepening knowledge on the primal molecular events triggering the toxic stimulus may be relevant to better understand the mechanisms of action of mycotoxins. The present work presents the use of in silico approaches in studying the mycotoxins toxicodynamics, and discusses how they may contribute in widening the background of knowledge. A particular emphasis has been posed on the methods accounting the molecular initiating events of toxic action. In more details, the key concepts and challenges of mycotoxins toxicology have been introduced. Then, topical case studies have been presented and some possible practical implementations of studying mycotoxins toxicodynamics have been discussed
Forthcoming Challenges in Mycotoxins Toxicology Research for Safer Food—A Need for Multi-Omics Approach
No full textThe presence of mycotoxins in food represents a severe threat for public health and welfare, and poses relevant research challenges in the food toxicology field. Nowadays, food toxicologists have to provide answers to food-related toxicological issues, but at the same time they should provide the appropriate knowledge in background to effectively support the evidence-based decision-making in food safety. Therefore, keeping in mind that regulatory actions should be based on sound scientific findings, the present opinion addresses the main challenges in providing reliable data for supporting the risk assessment of foodborne mycotoxins
An In Silico Framework to Mine Bioactive Peptides from Annotated Proteomes: A Case Study on Pancreatic Alpha Amylase Inhibitory Peptides from Algae and Cyanobacteria
No full textBioactive peptides may exert beneficial activities in living organisms such as the regulation of glucose metabolism through the inhibition of alpha amylases. Algae and cyanobacteria are gaining a growing interest for their health-promoting properties, and possible effects on glucose metabolism have been described, although the underlying mechanisms need clarification. This study proposes a computer-driven workflow for a proteome-wide mining of alpha amylase inhibitory peptides from the proteome of Chlorella vulgaris, Auxenochlorella protothecoides and Aphanizomenon flos-aquae. Overall, this work presents an innovative and versatile approach to support the identification of bioactive peptides in annotated proteomes. The study: (i) highlighted the presence of alpha amylase inhibitory peptides within the proteomes under investigation (including ELS, which is among the most potent inhibitory tripeptides identified so far); (ii) mechanistically investigated the possible mechanisms of action; and (iii) prioritized further dedicated investigation on the proteome of C. vulgaris and A. flos-aquae, and on CSSL and PGG sequences
Virtual display of targets: A new level to rise the current understanding of ochratoxin A toxicity from a molecular standpoint
No full text: Ochratoxin A (OTA) is a mycotoxin spread worldwide contaminating several food and feed commodities and rising concerns for humans and animals. OTA toxicity has been thoroughly assessed over the last 60 years revealing a variety of adverse effects, including nephrotoxicity, hepatotoxicity and possible carcinogenicity. However, the underpinning mechanisms of action have yet to be completely displayed and understood. In this framework, we applied a virtual pipeline based on molecular docking, dynamics and umbrella simulations to display new OTA potential targets. The results collected consistently identified OGFOD1, a key player in protein translation, as possibly inhibited by OTA and its 2'R diastereomer. This is consistent with the current knowledge of OTA's molecular toxicology and may fill some gaps from a mechanistic standpoint. This could pave the way for further dedicated analysis focusing their attention on the OTA-OGFOD1 interaction, expanding the current understanding of OTA toxicity at a molecular level
Molecular modelling approach to evaluate poisoning of topoisomerase I by alternariol derivatives
No full textAlternaria 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 studie
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