Abstract
Analysis of molecular interaction fields based on the published crystal structure of thapsigargin bound to the sarco/endoplasmatic reticulum Ca(2+)-ATPase and analysis of the volume and shape of the ligand binding site and of the SERCA-thapsigargin interactions have enabled design of two new compounds inhibiting SERCA in the subpicomolar range. The two inhibitors were synthesized using (S)-carvone as starting material and found to be 3 and 10 times more potent than thapsigargin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Azulenes / chemical synthesis*
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Azulenes / chemistry
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Binding Sites
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Calcium-Transporting ATPases / antagonists & inhibitors*
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Calcium-Transporting ATPases / chemistry*
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Endoplasmic Reticulum / enzymology*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Ligands
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Models, Molecular*
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Sarcoplasmic Reticulum / enzymology
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Stereoisomerism
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Thapsigargin / chemistry*
Substances
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2-methylbut-2-enoic acid 4-butyryloxy-6-ethoxy-3,3a-dihydroxy-3,6,9-trimethyl-2-oxododecahydroazuleno(4,5-b)furan-8-yl ester
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2-methylbut-2-enoic acid 6-acetoxy-4-butyryloxy-3,3a-dihydroxy-3,6,9-trimethyl-2-oxododecahydroazuleno(4,5-b)furan-8-yl ester
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Azulenes
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Enzyme Inhibitors
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Ligands
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Thapsigargin
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Calcium-Transporting ATPases