In order to explore the structure-activity correlation of a series of β-aminoketone analogs as inhibitors of thyroid hormone receptor (TR), a set of three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), for the first time, were developed in the present work. The best CoMFA model with steric and electrostatic fields exhibited [Formula: see text], [Formula: see text] for TRβ, and [Formula: see text], [Formula: see text] for TRα. 3D contour maps produced from the optimal models were further analyzed individually, which provide the areas in space where interactive fields would affect the inhibitory activity. In addition, the binding modes of inhibitors at the active site of TRs were examined using molecular docking, the results indicated that this series of inhibitors fit into the active site of TRs by forming hydrogen bonding and electrostatic interactions. The docking studies also revealed that Leu305, Val458 for TRβ, and Asp407 for TRα are showing hydrogen bonds with the most active inhibitors. In any case, the 3D-QSAR models combined with the binding information will serve as a useful approach to explore the chemical space for improving the activity of TRβ and TRα inhibitors.
Keywords: CoMFA; CoMSIA; TRα; TRβ; molecular docking.