Anti-androgen activity of polybrominated diphenyl ethers determined by comparative molecular similarity indices and molecular docking

Some polybrominated diphenyl ethers (PBDEs) may have endocrine-disrupting (ED) potencies. In this study, molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) were performed to explore the possible anti-androgenicity of PBDEs. Based on the alignment generated by docking conformations, a highly predictive comparative molecular similarity indices analysis (CoMSIA) model was developed with q² value of 0.642 and r² value of 0.973. The contributions of the steric, electrostatic, hydrophobic fields to the CoMSIA model are 13.1%, 61.0% and 25.9%, respectively. Br substitutions which are at meta and para positions of PBDEs will be unfavorable for androgen receptor (AR) antagonism and ortho Br substitutions for PBDEs are favorable for anti-androgen activity. Mapping the 3D-QSAR models to the active site of the AR provides new insight into the AR-PBDEs interaction. CoMSIA field contributions showed good consistency with structural features of the AR binding site and can be used to predict anti-androgen activities of other PBDE congeners. © 2009 Elsevier Ltd. All rights reserved.