Abstract
Dityrosine is the product of oxidation that has been linked to a number of serious pathological conditions. Evidence indicates that high amounts of dityrosine exist in oxidized milk powders and some milk related foodstuffs, further reducing the nutritional value of oxidized proteins. Therefore, we hypothesize that some receptors related to special diseases would be targets for dityrosine. However, the mechanisms of the interaction of dityrosine with probable targets are still unknown. In the present work, an inverse virtual screening approach was performed to screen possible novel targets for dityrosine. Molecular docking studies were performed on a panel of targets extracted from the potential drug target database (PDTD) to optimize and validate the screening results. Firstly, two different conformations cis- and trans- were found for dityrosine during minimization. Moreover, Tubulin (αT) (−11.0 kcal/mol) was identified as a target for cis-dityrosine (CDT), targets including αT (−11.2 kcal/mol) and thyroid hormone receptor beta-1 (−10.7 kcal/mol) presented high binding affinities for trans-dityrosine (TDT). Furthermore, in order to provide binding complexes with higher precision, the three docked systems were further refined by performing thermo dynamic simulations. A series of techniques for searching for the most stable binding pose and the calculation of binding free energy are elaborately provided in this work. The major interactions between these targets and dityrosine were hydrophobic, electrostatic and hydrogen bonding. The application of inverse virtual screening method may facilitate the prediction of unknown targets for known ligands, and direct future experimental assays.
Highlights
Proteins represent major targets for free radicals arising from oxygen reduction in vivo, which would be generated as a result of normal cellular metabolism and external stimulus, including environmental agents, such as metal ions and radiation
In this paper, an in silico inverse virtual screening approach was performed on dityrosine in an attempt to evaluate the possible interaction between dityrosine and targets that have been recognized as participants in different diseases and find possible binding conformations to direct experimental assays
In the class of nuclear receptors (Table S2), Lac Repressor (LacR) exhibits the best binding affinity for CDT, possessing score of −9.1 kcal/mol, Peroxisome proliferator activated receptor delta, Retinoic acid receptor RXR-alpha, Nuclear Vitamin D Receptor, Thyroid hormone receptor Alpha-1, Hepatocyte nuclear factor 4-gamma, Cellular Retinoic-Acid-Binding Protein Type II, and Liver X receptor alpha might interact with CDT, with binding scores of −8.7 kcal/mol, −8.4 kcal/mol, −8.3 kcal/mol, −8.2 kcal/mol, −8.2 kcal/mol, −8.0 kcal/mol and −8.0 kcal/mol, respectively
Summary
Proteins represent major targets for free radicals arising from oxygen reduction in vivo, which would be generated as a result of normal cellular metabolism and external stimulus, including environmental agents, such as metal ions and radiation. During food processing and storage, oxidized protein products (OPPs), such as protein carbonyls, methionine sulfoxide, and dityrosine, would be generated as a response to heat treatment, oxygen and light exposure, further leading to a decrease of product quality, safety, and nutritional value [4,5]. Dityrosine is a useful marker for assessing oxidative damage to proteins [13,14], which can be generated during a normal physiological process in specialized cases and as a result of exposure to environmental agents (ultraviolet irradiation, radicals, NO2, and lipid hydroperoxides). Based on the previous publications, it is assumed that dityrosine may result in potential damage to food nutrition and the human body, some related proteins might be the targets for dityrosine. In this paper, an in silico inverse virtual screening approach was performed on dityrosine in an attempt to evaluate the possible interaction between dityrosine and targets that have been recognized as participants in different diseases and find possible binding conformations to direct experimental assays
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