Analysis of Ah receptor binding affinities of polybrominated diphenyl ethers via in silico molecular docking and 3D-QSAR

Abstract

Polybrominated diphenyl ethers (PBDEs) have become ubiquitous contaminations due to their use as flame retardants. The structural similarity of PBDE to some dioxin-like compounds suggested that they may share similar toxicological effects: they might activate the aryl hydrocarbon receptor (AhR) signal transduction pathway and thus might have adverse effects on wildlife and humans. In this study, in silico computational workflow combining molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) was performed to investigate the binding interactions between PBDEs and AhR and the structural features affecting the AhR binding affinity of PBDE. The molecular docking showed that hydrogen-bond and hydrophobic interactions were the major driving forces for the binding of ligands to AhR, and several key amino acid residues were also identified. The CoMSIA model was developed from the conformations obtained from molecular docking and exhibited satisfactory results as q ² of 0.605 and r ² of 0.996. Furthermore, the derived model had good robustness and statistical significance in both internal and external validations. The 3D contour maps generated from CoMSIA provided important structural features influence the binding affinity. The obtained results were beneficial to better understand the toxicological mechanism of PBDEs.

Keywords:

• PBDEs
• Ah receptor
• 3D-QSAR
• CoMSIA
• molecular docking

Acknowledgements

This work was supported by the National Natural Science Foundation of P.R. China (grant 20737001). The authors also greatly appreciate Dr Huifeng Wu (Yantai Institute of Coastal Zone Research, Chinese Academy of Science) for supplying AhR structure. All authors thank anonymous reviewers and editors for their valuable suggestions on revising and improving the work.