Computer-aided identification of novel protein targets of bisphenol A

• This study states that the bisphenol A may interact with other targets different from the estrogen receptor.
• Bisphenol A seemed to interact with proteins involved in several high prevalence diseases.
• The proteins dual specificity protein kinases CLK4, CLK1 and CLK2 showed the best in silico affinity by bisphenol A.
• The validation showed that the in silico docking protocol reproduces well the bisphenol A pose on the crystallographic complex with ERR-gamma.
• Bisphenol A toxicological effects could be explained through its interactions with key proteins in signaling pathways.

The xenoestrogen bisphenol A (2,2-bis-(p-hydroxyphenyl)-2-propane, BPA) is a known endocrine-disrupting chemical used in the fabrication of plastics, resins and flame retardants, that can be found throughout the environment and in numerous every day products. Human exposure to this chemical is extensive and generally occurs via oral route because it leaches from the food and beverage containers that contain it. Although most of the effects related to BPA exposure have been linked to the activation of the estrogen receptor (ER), the mechanisms of the interaction of BPA with protein targets different from ER are still unknown. Therefore, the objective of this work was to use a bioinformatics approach to identify possible new targets for BPA. Docking studies were performed between the optimized structure of BPA and 271 proteins related to different biochemical processes, as selected by text-mining. Refinement docking experiments and conformational analyses were carried out using LigandScout 3.0 for the proteins selected through the affinity ranking (lower than −8.0 kcal/mol). Several proteins including ERR gamma (−9.9 kcal/mol), and dual specificity protein kinases CLK-4 (−9.5 kcal/mol), CLK-1 (−9.1 kcal/mol) and CLK-2 (−9.0 kcal/mol) presented great in silico binding affinities for BPA. The interactions between those proteins and BPA were mostly hydrophobic with the presence of some hydrogen bonds formed by leucine and asparagine residues. Therefore, this study suggests that this endocrine disruptor may have other targets different from the ER.

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