title: Predicting anti-androgenic activity of bisphenols using molecular docking and quantitative structure-activity relationships.
abstract: Both in vivo and in vitro assay indicated that bisphenols can inhibit the androgen receptor. However, the underlying antagonistic mechanism is unclear. In this study, molecular docking was employed to probe the interaction mechanism between bisphenols and human androgen receptor (hAR). The binding pattern of ligands in hAR crystal structures was also analyzed. Results show that hydrogen bonding and hydrophobic interactions are the dominant interactions between the ligands and hAR. The critical amino acid residues involved in forming hydrogen bonding between bisphenols and hAR is Asn 705 and Gln 711. Furthermore, appropriate molecular structural descriptors were selected to characterize the non-bonded interactions. Stepwise multiple linear regressions (MLR) analysis was employed to develop quantitative structure-activity relationship (QSAR) models for predicting the anti-androgenic activity of bisphenols. Based on the QSAR development and validation guideline issued by OECD, the goodness-of-fit, robustness and predictive ability of constructed QSAR model were assessed. The model application domain was characterized by the Euclidean distance and Williams plot. The mechanisms of the constructed model were also interpreted based on the selected molecular descriptors i.e. the number of hydroxyl groups (nROH), the most positive values of the molecular surface potential (Vs,max) and the lowest unoccupied molecular orbital energy (ELUMO). Finally, based on the model developed, the data gap for other twenty-six bisphenols on their anti-androgenic activity was filled. The predicted results indicated that the anti-androgenic activity of seven bisphenols was higher than that of bisphenol A.
authors: Nanjing Institute of Environmental Science, Ministry of Environmental Protection, Nanjing, 210042, China.
authors: Xianhai
authors: X
authors: Yang
authors: Jiangsu Key Laboratory of Chemical Pollution Control and Resources Reuse, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, China.
authors: Huihui
authors: H
authors: Liu
authors: Nanjing Institute of Environmental Science, Ministry of Environmental Protection, Nanjing, 210042, China; The College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 210009, China.
authors: Qian
authors: Q
authors: Yang
authors: Nanjing Institute of Environmental Science, Ministry of Environmental Protection, Nanjing, 210042, China. Electronic address: ljn@nies.org.
authors: Jining
authors: J
authors: Liu
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, 116024, China. Electronic address: jwchen@dlut.edu.cn.
authors: Jingwen
authors: J
authors: Chen
authors: Nanjing Institute of Environmental Science, Ministry of Environmental Protection, Nanjing, 210042, China.
authors: Lili
authors: L
authors: Shi
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D008024:Ligands; D010636:Phenols; D011944:Receptors, Androgen
keywords: Anti-androgenic activity; Bisphenols; Endocrine disrupting chemical (EDC); Human androgen receptor (hAR); Molecular docking; Quantitative structure-activity relationships (QSAR)