article · Journal of Applied Toxicology
Polychlorinated dibenzo-p-dioxins are environmental pollutants suspected of causing harmful toxic effects in humans and wildlife through endocrine disruption. To investigate the molecular mechanisms involved, computational molecular docking simulations were conducted on twelve nuclear receptors. The analysis identified androgen receptors, estrogen receptors alpha and beta, glucocorticoid receptors, and thyroid hormone receptors alpha and beta as the most probable targets for dioxin binding. The pollutant molecules successfully mimicked the interaction modes of natural and synthetic ligands within the active sites of these proteins. Stable complexes formed via electrostatic, van der Waals, pi-effect, and hydrophobic bonds with key amino acid residues. A high degree of residue overlap was observed between dioxin bindings and reference compounds such as dihydrotestosterone, 17beta-estradiol, and cortisol, providing structural evidence for how dioxins disrupt endocrine functions.
Understanding how industrial pollutants interfere with natural hormone functions is vital for assessing human and animal health risks. This computational research clarifies the precise molecular interactions through which dioxins bind to key hormonal receptors, supporting better toxicity screening and regulatory risk evaluations of persistent environmental contaminants.
The computational findings represent early-stage theoretical research that could inform toxicological profiling, chemical safety assessments, and environmental risk models used by regulatory agencies or chemical safety consultants. However, the abstract does not indicate a direct product development or commercialisation pathway.
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Polychlorinated dibenzo-p-dioxins (PCDDs) are hypothesized to exert their toxic effects in wildlife and humans via endocrine disruption. However, very scanty information is available on the underlying molecular interactions that trigger this disruption. In this study, molecular docking simulation was used to predict the susceptibility of 12 nuclear receptors to disruption via PCDD bindings. Findings revealed that androgen (AR and AR an), estrogen (ER α and ER β), glucocorticoid (GR) and thyroid hormone (TR α and TR β) receptors are the most probable protein targets that bind to PCDDs. Further molecular docking analyses showed that PCDD molecules mimic the modes of interaction observed for the co-crystallized ligands of the affected receptors, resulting in the formation of ligand-receptor complexes that were stabilized through electrostatic, van der Waals, pi-effect and hydrophobic interactions with 18, 17, 17, 16, 18, eight and four amino acid residues in the active sites of AR, AR an, ER α, ER β, GR, TR α and TR β respectively. The commonalities of these interacting amino acid residues with those utilized by dihydrotestosterone in AR, bicalutamide in AR an, 17β-estradiol in ER α, 17β-estradiol in ER β, cortisol in GR, thyromimetic GC-1 in TR α and thyromimetic GC-1 in TR β are 86%, 74%, 94%, 80%, 82%, 50% and 43% respectively. The results obtained in this study provide supporting evidence that PCDD molecules may interfere with the endocrine system via binding interactions with some vital amino acid residues in the binding pockets of AR, ERs, GRs and TRs.
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DOI: 10.1002/jat.4039
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