Structural requirements for inhibitory effects of bisphenols on the activity of the sarco/endoplasmic reticulum calcium ATPase

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• 作者：Matthew Woeste ; Jeffrey Steller ; Emily Hofmann ; Taylor Kidd ; Rahul Patel ; Kevin Connolly ; Manori Jayasinghe ; Stefan Paula ; ^{paulas1@nku.edu}
• 关键词：Calcium homeostasis ; Fluorescence imaging ; Bisphenol A ; Calcium ion transport ; Computational docking ; Toxicity ; ATPase activity assay
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 July, 2013
• 年：2013
• 卷：21
• 期：13
• 页码：3927-3933
• 全文大小：1603 K

文摘

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.