Predictive insight into the relationship between AhR binding property and toxicity of polybrominated diphenyl ethers by PLS-derived QSAR

• Published in: Toxicology letters Vol. 208; no. 3; pp. 269 - 274
• Main Authors: Gu, Chenggang, Goodarzi, Mohammad, Yang, Xinglun, Bian, Yongrong, Sun, Cheng, Jiang, Xin
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 05.02.2012; Elsevier
• Subjects: AhR binding affinity; binding capacity; Biological and medical sciences; bromination; DFT; electrostatic interactions; Halogenated Diphenyl Ethers - chemistry; Halogenated Diphenyl Ethers - metabolism; Halogenated Diphenyl Ethers - toxicity; Medical sciences; PLS; Polybrominated diphenyl ether; polybrominated diphenyl ethers; polychlorinated biphenyls; prediction; Protein Binding; Quantitative Structure-Activity Relationship; quantitative structure-activity relationships; Receptors, Aryl Hydrocarbon - chemistry; Receptors, Aryl Hydrocarbon - metabolism; topology; Toxicity; Toxicology; WHIM; AhR binding affinity; DFT; Polybrominated diphenyl ether; Toxicity; WHIM; PLS; Aryl hydrocarbon receptor; Binding capacity; Structure activity relation; Prediction; Affinity; Bromine Organic compounds
• ISSN: 0378-4274; 1879-3169; 1879-3169
• DOI: 10.1016/j.toxlet.2011.11.010

► A simple but potent QSAR was successfully developed for PBDE toxicity. ► Dispersion and electrostatic interactions were reflective of AhR binding property. ► Dispersion interaction was suggested to be dominant in AhR binding affinity. ► Bromination at para- and meta (particularly 3,3′-)-sites was favorable for toxicity. ► Relationship between AhR binding property and toxicity was reasonably explained. Polybrominated diphenyl ethers (PBDEs) are experimentally indicated to be capable of binding to the cytosolic aryl hydrocarbon receptor (AhR) and show a weak or moderate toxicity. However, little is yet known about the AhR-mediated toxicology. To fully evaluate the structural effects of PBDE ligand on AhR binding affinity and toxicity, quantitative structure–activity relationships (QSARs) were developed by PLS analysis. In this study, a simple but potent QSAR that was qualified with much better or comparable performance of prediction was optimally established for PBDE toxicity. With QSAR analysis, the AhR binding property was carefully described to reflect the origin of AhR binding affinity. Besides the effects from topological characters, the dispersion and electrostatic interactions were of indispensability for AhR binding affinity whereas the dispersion was further suggested to be dominant. The structural requirement for AhR binding affinity and toxicity was also investigated. As was similarly observed for polychlorinated biphenyls (PCBs), the preferential bromination at para- and meta (particularly 3,3′-)-sites was confirmed as a key determinant to improve the AhR binding affinity and the toxicity of PBDEs.