Models for the binding of amiodarone to the thyroid hormone receptor |
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Authors: | David K. Chalmers Sharon L. A. Munro Magdy N. Iskander David J. Craik |
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Affiliation: | (1) School of Pharmaceutical Chemistry, Victorian College of Pharmacy Ltd., 381 Royal Parade, 3052 Parkville, Vic., Australia |
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Abstract: | Summary The antiarrhythmic drug amiodarone has recently been characterized as the first known thyroid hormone antagonist. Its mode of interaction with the thyroid hormone receptor is therefore of interest. A computational analysis of the conformational flexibility of amiodarone using molecular mechanics and the semiempirical molecular orbital method AM1 has been performed. The molecular mechanics studies show that the low-energy conformations of the benzoylbenzofuran portion of amiodarone can be grouped into 4 distinct classes, while the diethylaminoethoxy side chain is extremely flexible. Conformers representative of the 4 low-energy classes were fitted to an extended thyroid hormone receptor model. Four independent modes in which amiodarone could bind to the thyroid hormone receptor site were evaluated. |
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Keywords: | Molecular graphics Conformational search Molecular mechanics Semiempirical molecular orbital calculations |
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