1,721,068 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
How computational methods try to disclose the estrogen receptor secrecy - Modelling the flexibility
No full textThe Estrogen Receptor (ER) is a ligand activated transcription factor involved in numerous fundamental biological processes as in many important diseases and malfunctions. Since 1998, when the first structure of the ER ligand binding domain complexed with 17 beta-estradiol (E2) was released, the number of ER alpha and ER beta crystallographic structures constantly increased. Nevertheless, little is still known about several fundamental events that govern the regular biological activity, or that modulate the transcription response following the interaction of the receptor with xenobiotic compounds. Moreover, the peculiar flexibility of the receptor characterized by two levels of conformational changes, i.e slight adjustments of binding pocket residues side chains, and more significant displacement of helix 12, moving from a close/agonist-like to an open/antagonist-like position, makes experimental approaches unable to properly describe and predict the receptor conformational equilibrium. Which is the most probable structure of the unbound receptor? How do biological ligands enter the receptor? How does the tissue-related pull of coactivators and corepressors affect the puzzling conformational equilibrium of the receptor? Since most of these questions still do not have an answer. A proper description of the structure-activity relationship and of the pharmacophoric properties of the binding pocket would be of paramount importance in order to design new agonist and antagonist molecules, and to understand how diverse xenobiotic compounds can alter the conformational equilibrium of the receptor, inducing estrogenic or anti-estrogenic effects. In this review we report the most relevant computational approaches, both theoretical and applicative, and the latest proposed models
Hint approach on Transthyretin folding/unfolding mechanism comprehension
No full textNon-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or temperature variations can compromise intramolecular stability generating misfolding or unfolding proteins with consequent impairment of functionality and the triggering of pathological states. The intramolecular HINT scoring function recently implemented and validated, is proposed as a rapid and sensitive method for the evaluation of different conformational states characterizing destabilization processes. In this work, the stability of Transthyretin, whose denaturation is related to amyloid fibril formation, is evaluated by generating multiple structural mutated models under different pH conditions in comparison with experimental data. These results suggest that the HINT scoring function can be used for an accurate and rapid evaluation and computational prediction of the effects of structural changes on any protein system
Docking new ligands having in hand poor experimental data. Estrogen receptor as a case study
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Preliminary hazard evaluation of androgen receptor-mediated endocrine-disrupting effects of thioxanthone metabolites through structure-based molecular docking.
No full textFoodstuff could be a vector for naturally occurring and/or unwanted dangerous substances that can act either as they are or after their bioactivation. The scientific community agrees that the metabolic activity of chemicals should be taken into account for proper risk assessment. Unfortunately, the in vitro evaluation of a metabolic panel and analytical/biochemical detection in food-safety assessment are very expensive and challenging because of the abundance of data to analyze. In this context, properly validated computational protocols could be a useful tool for making metabolic and binding/activity predictions. This strategy has been applied to thioxanthone photoinitiators (TX), identified as food contaminants, especially in infant formulas, as reported by the European Food Safety Authority in 2005. Their lipophilicity suggests rapid hepatic metabolism, but the currently available data only concern 2-ITX. We have predicted phase I metabolites for the TX class of compounds and defined their binding affinity for the AR ligand-binding pocket using a local model based on available information about metabolism and AR activity. Some metabolites should undergo further in vitro or/and in vivo toxicological evaluations because they have proved to be suitable as ligands for AR
Novel allosteric effectors of the tryptophan synthase a2b2 complex identified by computer assisted molecular modelling
No full textA new approach for investigating protein flexibility based on Constraint Logic Programming. The first application in the case of the estrogen receptor
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