Design of Active Site-Directed Iodothyronine Deiodinase Ligands Using TBPA as a Binding Site Model
Rat liver microsomal type I iodothyronine deiodinase (ITH-D) accounts for the major part of the production of thyromimetically active L-T3 from L-T4 in euthyroid conditions. Therefore, structure-activity-relationships (SAR) were evaluated for various classes of enzyme ligands (ITH-analogues, dyes, flavonoids) which serve either as ITH-D substrates or inhibitors in vitro (1). We have previously reported that flavonoids, and other phenolic secondary metabolites of plants used in folk medicine for treatment of thyroidal diseases, are potent ITH-D inhibitors (2). Analysis of SAR for ITHmetabolites and ITH-analogues revealed that the ligand-binding site of the ITH-D exhibits high analogy to the serum ITH-transport protein, thyroxine-binding prealbumin (TBPA), with respect to essential structural requirements for ligands, in contrast to TBG or the nuclear T3-receptor, both of which show only minor similarity (3). The x-ray structures of ITHs, TBPA, and the T4-TBPA-complex were solved in high resolution (4–6). Therefore, these data for the T4-binding site of TBPA could be used for computer-graphic molecular modeling of the putative enzyme ligand binding site of the ITH-D. In order to test our previously developed hypothesis concerning the high similarity of both ligand binding sites (3,7–9), we tried to displace 125)I-labeled L-T4 from binding to hTBPA by competition with representative effectors of the ITH-D-reaction.
KeywordsLigand Binding Site Iodine Atom Phenolic Ring Binding Site Model Iopanoic Acid
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