title: Molecular docking and 3D-QSAR studies on the glucocorticoid receptor antagonistic activity of hydroxylated polychlorinated biphenyls.
abstract: The glucocorticoid receptor (GR) antagonistic activities of hydroxylated polychlorinated biphenyls (HO-PCBs) were recently characterised. To further explore the interactions between HO-PCBs and the GR, and to elucidate structural characteristics that influence the GR antagonistic activity of HO-PCBs, molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Comparative molecular similarity indices analysis (CoMSIA) was performed using both ligand- and receptor-based alignment schemes. Results generated from the receptor-based model were found to be more satisfactory, with q(2) of 0.632 and r(2) of 0.931 compared with those from the ligand-based model. Some internal validation strategies (e.g. cross-validation analysis, bootstrapping analysis and Y-randomisation) and an external validation method were used respectively to further assess the stability and predictive ability of the derived model. Graphical interpretation of the model provided some insights into the structural features that affected the GR antagonistic activity of HO-PCBs. Molecular docking studies revealed that some key residues were critical for ligand-receptor interactions by forming hydrogen bonds (Glu540) and hydrophobic interactions with ligands (Ile539, Val543 and Trp577). Although CoMSIA sometimes depends on the alignment of the molecules, the information provided is beneficial for predicting the GR antagonistic activities of HO-PCB homologues and is helpful for understanding the binding mechanisms of HO-PCBs to GR.
authors: a College of Environmental Science & Engineering , Huazhong University of Science & Technology , Wuhan , China.|b Research & Development Institute of Wuhan Iron & Steel Group , Wuhan , China.
authors: S
authors: S
authors: Liu
authors: c State Key Laboratory of Pollution Control and Resource Reuse , School of the Environment, Nanjing University , Nanjing , China.
authors: Y
authors: Y
authors: Luo
authors: d School of Civil and Environmental Engineering , Georgia Institute of Technology , Atlanta , GA , USA.
authors: J
authors: J
authors: Fu
authors: a College of Environmental Science & Engineering , Huazhong University of Science & Technology , Wuhan , China.
authors: J
authors: J
authors: Zhou
authors: e Division of Chemical Technology, Department of Chemistry , Aristotle University of Thessaloniki , Thessaloniki , Greece.
authors: G Z
authors: GZ
authors: Kyzas
mesh_terms: D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D006900:Hydroxylation; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D008024:Ligands; D011965:Receptors, Glucocorticoid; D011078:Polychlorinated Biphenyls
keywords: 3D-QSAR; CoMSIA; HO-PCBs; glucocorticoid receptor; molecular docking