title: In silico investigations of anti-androgen activity of polychlorinated biphenyls.
abstract: Polychlorinated biphenyls (PCBs) have attracted great concern as global environmental pollutants and representative endocrine disruptors. In this work, a molecular model study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations was performed to explore the structural requirement for the anti-androgen activities of PCBs and to reveal the binding mode between the PCBs and androgen receptor (AR). The best comparative molecular similarity indices analysis (CoMSIA) model, obtained from receptor-based alignment, shows leave-one-out cross-validated correlation coefficient (q(2)) of 0.665 and conventional correlation coefficient (R(2)) of 0.945. The developed model has a highly predictive ability in both internal and external validation. Furthermore, the interaction mechanisms of PCBs to AR were analyzed by molecular docking and MD simulation. Molecular docking indicated that all the PCBs in the data set docked in a hydrophobic pocket. The Binding free energies calculated by Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) not only exhibited a good correlation with the experimental activity, but also could explain the activity difference of the studied compounds. The binding free energy decomposition analysis indicates that the van der Waals interaction is the major driving force for the binding process.
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, PR China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Hongling
authors.initials: H
authors.lastname: Liu
authors.forename: Xiangping
authors.initials: X
authors.lastname: Qian
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Hongxia
authors.initials: H
authors.lastname: Yu
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D052244:Endocrine Disruptors / Q000737:chemistry / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D052244:Endocrine Disruptors; D011944:Receptors, Androgen; D011078:Polychlorinated Biphenyls