We established a novel screening method to survey endocrine-disrupting chemicals by means of in silico docking calculations. Endocrine disruptors target the human nuclear receptor, which bind a chemical in a pocket presenting in the ligand-binding domain (LBD). The LBD alters its conformation, depending upon the binding of either agonist or antagonist. We discovered that the chemicals can be differentiated into either agonist or antagonist by the docking calculations of the chemical for the LBD. We used the crystal structures of both agonist-bound LBDs and antagonist-bond LBDs as templates in the docking calculations, and estimated binding energies to discriminate between agonist and antagonist bindings. This agonist/antagonist differential-docking screening (AADS) method predicted, for example, 4-(1-adamantyl)phenol as an agonist of the human estrogen receptor α (hERα). Indeed, this compound, one of the essential raw materials for nanoporous organosilicate thin films, was confirmed to exhibit strong agonist activity in the reporter-gene assay for hERα with a high binding affinity. The AADS method is an approach that appears to foresee both the binding ability and the agonist/antagonist function of chemicals for the target nuclear receptors.
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