Computational Simulation And Validation On The Estrogenic And Thyroid Hormone Activities Of Some Organic Chemicals

The studies on the eco-toxicological effects of the environmental organic pollutants are of great importance to their ecological risk assessment. A number of organic compounds are released into the environment, most of which are suspicious endocrine disrupting chemicals (EDCs). Experimental determination of EDCs is costly, time-consuming, and restricted by lack of sufficiently pure chemicals, thus there is a need to develop high throughput screening method to screen suspicious EDCs. The purpose of the present study was to develop quantitative structure-activity relationship (QSAR) models for endocrine disrupting effects, to clarify the mechanism of the endocrine disrupting of exogenous compounds and to establish the relationships between the hormone-like effect and the molecular structure parameters by an integrated in silico and in vitro approach.A QSAR model for a series of xenoestrogens was developed based on the determined estrogenic activities (expressed by logRP) by partial least squares (PLS) regression. An independent external validation set was employed to evaluate the performance of the developed QSAR model. The estabilshed QSAR model had goodness-of-fit, robustness and predictivity. The leave-one-out cross-validation squared correlation coefficient (Q2L∞) was 0.90. The predicted logRP values were consistent with the observed values, with a root mean square error (RMSE) of 0.74 log units and the squared correlation coefficient (Q2EXT) was 0.78. The current QSAR model could be used to high-throughput screen xenoestrogens. The logRP value was related to polarizability, molecular size, shape profiles and intermolecular interactions.To further understand the mechanism of action, we explored the estrogenic activities of 20 anthraquinone derivatives (AQs). Molecular docking analysis showed that hydrogen bonding, hydrophobic and electrostatic interactions between the AQs molecules and estrogen receptor alpha (ERa) governed the estrogenic activities of the AQs. The recombinant yeast-based assay was employed to determine the estrogenic activities of the 20 AQs. Based on the observed interactions between the AQs and ERa, the polarizability term (πl), the binding energy (Ebinding), the average molecular polarizability (a), the most negative formal charge in the molecule (q) and the average of the negative potentials on the molecular surface (Vs-) were adopted to develop a QSAR model, which had good robustness, predictive ability and mechanism interpretability. The average molecular polarizability (a) is the main molecular structural factor. The AQs molecule with greaterαvalue exerted higher estrogenic activity. Moreover, q and Vs-also affect the estrogenic activity. The results indicated that the estrogenic activity of the AQs depended on the partition ability of compounds into the bio-phase and the electrostatic interaction with the receptor.Molecular docking was adopted to simulate the interactions between 18 hydroxylated polybrominated diphenyl ethers (HO-PBDEs) and thyroid hormone receptors beta (TRβ). The results showed that the bindings to TRβare the key steps for the HO-PBDEs to exert their thyroid hormone activity, and hydrogen bonding, hydrophobic andπ-πinteractions were also found between the HO-PBDEs and TRβ. The thyroid hormone activities of the 18 HO-PBDEs were determined by the yeast two-hybrid assay. The 18 tested HO-PBDEs exhibit significant higher thyroid hormone activities than PBDEs (p< 0.05). Based on the observed mechanism of interactions, appropriate molecular structural parameters were adopted to develop a QSAR model. The number of bromine atoms (nBr) octanol/water partition coefficient (logΚow), aromaticity index (IA), energy of the highest occupied molecular orbital (EHomo), electrophilicity index (ω) and dipole moment (μ) were significant parameters explaining the thyroid hormone activity. The developed QSAR model had good robustness, predictive ability and mechanism interpretability. The partition ability of the HO-PBDEs into the bio-phase was an important factor governing their thyroid hormone activities. Non-planarity of HO-PBDEs facilitates the binding with TRβ. The HO-PBDEs with higher ability to accept proton (as indicated by ELUMO andω) tend to have weak H-bonding with the receptor, and lower thyroid hormone activities.