ONIOM study of the 4′-hydroxyl hydrogen bond acceptor/donor group nature in thyromimetics

β1-Selective thyroid receptor agonists constitute a therapeutic possibility as antiobesity and lipid-lowering agents. Thyroid receptor models were constructed from crystallographic structures and the acceptor/donor nature of 4′-hydroxyl group was investigated by the ONIOM method. All binding energies determined indicated the preference for the protonated form of amino acid residue His 381. Theoretical results confirmed experimental findings that the 4′-position requires a hydrogen bond acceptor/donor group. It also indicates that it should be an acceptor of hydrogen bond as amino acid residue His 381 is preferentially protonated. Also seem to indicate 4′-amino substituted thyromimetics as promising candidates for TR agonists, picturing them as possible alternatives to 4′-phenolic classical thyromimetics. 4′-amino substituted thyromimetics have displayed the closest interaction with protonated residue His 381 and the most stable ligand-LBD model system complex. This provides insight upon the design of novel TR agonists.