Diethylstilbestrol increases intracellular calcium in lens epithelial cells

Samadi, Abbas; Cenedella, Richard J.; Carlson, C. George

doi:10.1007/s00424-005-1398-2

Cited by 7 publications

(2 citation statements)

References 43 publications

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“…The loss of calcium homeostatis in the platelets may originate from inhibition of SERCA by TAM. In addition, there is evidence that diethylstilbestrol increases intracellular calcium in lens epithelial cells by inhibiting SERCA [48] and cataracts result from TG1inhibited SERCA upregulation [49,50]. We believe the evidence for off-site binding of SERMs to SERCA and the proposed impact that it has on calcium homeostatis leads to the reported adverse effects.…”

Section: Author Summarymentioning

confidence: 83%

In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators

2005

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Early identification of adverse effect of preclinical and commercial drugs is crucial in developing highly efficient therapeutics, since unexpected adverse drug effects account for one-third of all drug failures in drug development. To correlate protein-drug interactions at the molecule level with their clinical outcomes at the organism level, we have developed an integrated approach to studying protein-ligand interactions on a structural proteome-wide scale by combining protein functional site similarity search, small molecule screening, and protein-ligand binding affinity profile analysis. By applying this methodology, we have elucidated a possible molecular mechanism for the previously observed, but molecularly uncharacterized, side effect of selective estrogen receptor modulators (SERMs). The side effect involves the inhibition of the Sacroplasmic Reticulum Ca2þ ion channel ATPase protein (SERCA) transmembrane domain. The prediction provides molecular insight into reducing the adverse effect of SERMs and is supported by clinical and in vitro observations. The strategy used in this case study is being applied to discover off-targets for other commercially available pharmaceuticals. The process can be included in a drug discovery pipeline in an effort to optimize drug leads and reduce unwanted side effects.

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Section: Author Summarymentioning

confidence: 83%

In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators

2005

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“…The loss of calcium homeostatis in the platelets may originate from inhibition of SERCA by TAM. In addition, there is evidence that diethylstilbestrol increases intracellular calcium in lens epithelial cells by inhibiting SERCA [48] and cataracts result from TG1-inhibited SERCA upregulation [49,50]. We believe the evidence for off-site binding of SERMs to SERCA and the proposed impact that it has on calcium homeostatis leads to the reported adverse effects.…”

Section: Resultsmentioning

confidence: 96%

In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators

2007

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Early identification of adverse effect of preclinical and commercial drugs is crucial in developing highly efficient therapeutics, since unexpected adverse drug effects account for one-third of all drug failures in drug development. To correlate protein–drug interactions at the molecule level with their clinical outcomes at the organism level, we have developed an integrated approach to studying protein–ligand interactions on a structural proteome-wide scale by combining protein functional site similarity search, small molecule screening, and protein–ligand binding affinity profile analysis. By applying this methodology, we have elucidated a possible molecular mechanism for the previously observed, but molecularly uncharacterized, side effect of selective estrogen receptor modulators (SERMs). The side effect involves the inhibition of the Sacroplasmic Reticulum Ca2+ ion channel ATPase protein (SERCA) transmembrane domain. The prediction provides molecular insight into reducing the adverse effect of SERMs and is supported by clinical and in vitro observations. The strategy used in this case study is being applied to discover off-targets for other commercially available pharmaceuticals. The process can be included in a drug discovery pipeline in an effort to optimize drug leads and reduce unwanted side effects.

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Steroid-induced cataract

Samadi¹

2010

Ocular Disease

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Diethylstilbestrol increases intracellular calcium in lens epithelial cells

Cited by 7 publications

References 43 publications

In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators

In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators

In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators

Steroid-induced cataract

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