title: Structural requirements for inhibitory effects of bisphenols on the activity of the sarco/endoplasmic reticulum calcium ATPase.
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.
authors: Department of Chemistry, Dorothy Westerman Herrmann Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors: Matthew
authors: M
authors: Woeste
authors: Jeffrey
authors: J
authors: Steller
authors: Emily
authors: E
authors: Hofmann
authors: Taylor
authors: T
authors: Kidd
authors: Rahul
authors: R
authors: Patel
authors: Kevin
authors: K
authors: Connolly
authors: Manori
authors: M
authors: Jayasinghe
authors: Stefan
authors: S
authors: Paula
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000009:adverse effects* / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D052244:Endocrine Disruptors / Q000009:adverse effects / Q000737:chemistry; D004785:Environmental Pollutants / Q000009:adverse effects* / Q000737:chemistry*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D061848:Optical Imaging; D010636:Phenols / Q000009:adverse effects* / Q000737:chemistry*; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002118:Calcium; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D010636:Phenols; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C006780:bisphenol A; D000098826:Bisphenol A Compounds
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