Structural basis for androgen receptor agonists and antagonists: Interaction of SPEED 98-listed chemicals and related compounds with the androgen receptor based on an in vitro reporter gene assay and 3D-QSAR

The androgen receptor (AR) activity of listed chemicals, so called SPEED 98, by the Ministry of the Environment, Japan, and structurally related chemicals was characterized using MDA-kb2 human breast cancer cells stably expressing an androgen-responsive luciferase reporter gene, MMTV-luc. Since our results suggested that chemicals with diverse chemical structures were capable of disrupting the endocrine systems mediated by AR, a comparative molecular field analysis (CoMFA) model was developed to analyze the structural requirements necessary to disrupt AR function. A significant CoMFA model with r2 = 0.825 and q2 = 0.332 was developed for AR antagonist activity of 35 pure antagonists excluding procymidone. On the other hand, a good CoMFA model with r2 = 0.983 and q2 = 0.555 was obtained for antagonist activity of 13 chemicals with both agonist and antagonist activities. The steric and electrostatic properties were sufficient to describe the structural requirements for AR antagonist activity. In addition, the structural difference of AR agonists and antagonists was explained based on CoMFA results and the AR-LBD crystal structure. As several ERα agonists such as diethylstilbestrol (DES) acted as AR antagonists, the surface area of the AR ligand-binding domain (LBD) was compared with that of the ERα-LBD based on their reported crystal structures to analyze how those ligands interact with LBDs. The surface area of AR-LBD was shown to be smaller than that of ERα-LBD and therefore compounds with both estrogenic and antiandrogenic activities can fit well into the ERα-LBD but may protrude from the AR-LBD. It is likely that this subtle difference of the surface areas of the LBDs determines whether an ERα agonist acts as an AR antagonist or an agonist.

The analysis of the structural requirements necessary to disrupt androgen receptor (AR) function shows that the steric and electrostatic properties were sufficient to describe the structural requirements for AR antagonist activity and the structural difference of AR agonists and antagonists was explained based on 3D-QSAR results and the AR crystal structure. The subtle difference of the surface areas of the ligand binding domain between AR and ER determines whether an ER agonist acts as an AR antagonist or an agonist.Figure optionsDownload as PowerPoint slide