1. Structural requirements for inhibitory effects of bisphenols on the activity of the sarco/endoplasmic reticulum calcium ATPase.
- Author
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Woeste M, Steller J, Hofmann E, Kidd T, Patel R, Connolly K, Jayasinghe M, and Paula S
- Subjects
- Animals, Calcium metabolism, Cells, Cultured, Endocrine Disruptors adverse effects, Endocrine Disruptors chemistry, Fibroblasts drug effects, Fibroblasts enzymology, Fibroblasts metabolism, Humans, Molecular Docking Simulation, Optical Imaging, Rabbits, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism, Structure-Activity Relationship, Benzhydryl Compounds adverse effects, Benzhydryl Compounds chemistry, Environmental Pollutants adverse effects, Environmental Pollutants chemistry, Phenols adverse effects, Phenols chemistry, Sarcoplasmic Reticulum Calcium-Transporting ATPases antagonists & inhibitors
- Abstract
Bisphenols (BPs) are a class of small organic compounds with widespread industrial applications. Previous studies have identified several BPs that interfere with the activity of the ion-translocating enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). In order to define the molecular determinants of BP-mediated SERCA inhibition, we conducted enzyme activity assays with rabbit SERCA to determine the inhibitory potencies of 27 commercially available BPs, which were the basis for structure-activity relationships. The most potent BPs inhibited SERCA at low micromolar concentrations and carried at their two phenyl rings multiple non-polar substituents, such as small alkyl groups or halides. Furthermore, the presence of methyl groups or a cyclohexyl group at the central carbon atom connecting the two phenyl moieties correlated with good potencies. For a characterization and visualization of enzyme/inhibitor interactions, molecular docking was performed, which suggested that hydrogen bonding with Asp254 and hydrophobic interactions were the major driving forces for BP binding to SERCA. Calcium imaging studies with a selection of BPs showed that these inhibitors were able to increase intracellular calcium levels in living human cells, a behavior consistent with that of a SERCA inhibitor., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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