Mechanism of Thyroxine Deiodination by Naphthyl-Based Iodothyronine Deiodinase Mimics and the Halogen Bonding Role: A DFT Investigation

This paper deals with a systematic density functional theory (DFT) study aiming to unravel the mechanism of the thyroxine (T4) conversion into 3,3′,5‐triiodothyronine (rT3) by using different bio‐inspired naphthyl‐based models, which are able to reproduce the catalytic functions of the type‐3 deiodinase ID‐3. Such naphthalenes, having two selenols, two thiols, and a selenol–thiol pair in peri positions, which were previously synthesized and tested in their deiodinase activity, are able to remove iodine selectively from the inner ring of T4 to produce rT3. Calculations were performed including also an imidazole ring that, mimicking the role of the His residue, plays an essential role deprotonating the selenol/thiol moiety. For all the used complexes, the calculated potential energy surfaces show that the reaction proceeds via an intermediate, characterized by the presence of a XIC (X=Se, S) halogen bond, whose transformation into a subsequent intermediate in which the CI bond is definitively cleaved and the incipient XI bond is formed represents the rate‐determining step of the whole process. The calculated trend in the barrier heights of the corresponding transition states allows us to rationalize the experimentally observed superior deiodinase activity of the naphthyl‐based compound with two selenol groups. The role of the peri interactions between chalcogen atoms appears to be less prominent in determining the deiodination activity. Role models: DFT was used to investigate the mechanism of thyroxine (T4) conversion into 3,3′,5‐triiodothyronine (rT3) by using different bio‐inspired naphthtyl‐based models that are able to reproduce the catalytic functions of the type‐3 deiodinase ID‐3 (see figure). Calculations included an imidazole ring that plays an essential role as deprotonating agent by mimicking the role of the His residue.