Mitigating the Adverse Effects of Polychlorinated Biphenyl Derivatives on Estrogenic Activity via Molecular Modification Techniques
Abstract
:1. Introduction
2. Materials and Methods
2.1. Construction of a 3D-QSAR Model and Molecular Modification of PCBs with Low Estrogenic Activity
2.2. Mechanism Analysis Method for Determining the Anti-Oestrogenic Activity of PCBs before and after Modification Based on Molecular Docking
3. Results and Discussion
3.1. Molecular Substitution Design of Low Anti-Oestrogenic Activity of PCB Derivatives Based on the CoMSIA Model 3D Contour Map
3.1.1. Construction and Verification of the CoMSIA Model of Anti-Oestrogenic Activity of PCBs
3.1.2. Analysis of Factors Affecting the Anti-Oestrogenic Activity of PCB Molecules Based on the 3D Contour Map of the CoMSIA Model and the Modification Design of PCB Derivatives with a Low Stimulating Hormone
3.1.3. Prediction of the Anti-Oestrogenic Activity of PCB Derivatives and Evaluation of POPs
3.2. Analysis of the Underlying Mechanism That Caused Changes in the Anti-Oestrogenic Activity of PCB Derivatives Based on Molecular Docking Techniques
3.2.1. Analysis of the Molecular Docking Effect of PCB-44 Bound to hERα before and after Modification
3.2.2. Analysis of Amino Acid Residues Docked to hERα before and after Molecular Modification of PCBs
3.3. Validation in Oestrogenic Effect Mitigation of PCBs Based on Molecular Dynamics Simulations
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Abbreviations in English | Full English Name |
PCBs | Polychlorinated biphenyls |
POPs | Persistent organic pollutants |
E1 | Estrone |
E2 | 17β-estradiol |
3D-QSAR | Three-dimensional quantitative structure-activity relationship |
hERα | Human oestrogen receptor α |
REC20 | Estrogen Activity Indicators |
CoMSIA | Comparative molecular similarity index analysis |
n | Optimal number of principal components |
q2 | Cross-validation coefficient |
r2 | Non-cross-validation coefficient |
SEE | Standard deviation |
F | F-test value |
r2pred | external test coefficient |
SEP | Standard error of prediction |
Q2ext | External sample calibration complex correlation coefficient |
E | Electrostatic field |
H | Hydrophobic field |
S | Stereo field |
D | Hydrogen bond donor field |
A | Hydrogen bond acceptor field |
PDB | Protein Data Bank |
NCBI | National Centre for Biotechnology Information |
MD | Molecular docking |
logBCF | Bioconcentration factors |
logt1/2 | Biological Half-life |
logKOA | N-octanol/air partitioning coefficients |
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No. | Compounds | Observed Value |
---|---|---|
1a | 2,2′,5-Trichlorobiphenyl (PCB-18) | 5.006 |
2 a | 2,4,6-Trichlorobiphenyl (PCB-30) | 6.614 |
3 a | 2,2′,3,5′-Tetrachlorobiphenyl (PCB-44) | 8.158 |
4 a | 2,2′,5,5′-Tetrachlorobiphenyl (PCB-52) | 6.509 |
5 a | 2,2′,4,4′,5-Pentachlorobiphenyl (PCB-99) | 6.048 |
6 a | 2,2′,4,5,5′-Pentachlorobiphenyl (PCB-101) | 7.189 |
7 a | 2,3,3′,4′,6-Pentachlorobiphenyl (PCB-110) | 8.009 |
8 b | 2,2′,3,3′,4,4′-Hexachlorobiphenyl (PCB-128) | 7.073 |
9 b | 2,2′,4,5′,6-Pentachlorobiphenyl (PCB-103) | 7.770 |
10 b | 2,2′,4,5′-Tetrachlorobiphenyl (PCB-49) | 6.672 |
11 b | 2,4,4′-Trichlorobiphenyl (PCB-28) | 5.430 |
Model | n | q2 | r2 | SEE | F | r2pred | SEP | Q2ext | S | E | H | D | A |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CoMSIA | 3 | 0.665 | 0.991 | 0.146 | 114.424 | 0.902 | 0.206 | 0.904 | 0.50% | 85.70% | 13.70% | 0 | 0 |
Compounds | pREC20 | logBCF [33] | logt1/2 [36] | logKOA [37] | pEC50 [38] | |||||
---|---|---|---|---|---|---|---|---|---|---|
CoMSIA Pred. | Fall Rate (%) | CoMSIA | Change Rate (%) | CoMSIA | Change Rate (%) | CoMSIA | Change Rate (%) | CoMFA | Change Rate (%) | |
Target molecule PCB-44 | 8.158 | 4.542 | 0.94 | 9.318 | 4.327 | |||||
3-carboxyl-PCB-44 | 7.712 | 5.5 | 4.204 | −7.44 | 0.830 | −11.70 | 8.731 | −6.30 | 4.878 | 12.73 |
3-amino-PCB-44 | 7.009 | 14.1 | 4.042 | −11.01 | 0.694 | −26.17 | 8.210 | −11.89 | 3.943 | −8.87 |
3-vinyl-PCB-44 | 5.201 | 36.2 | 4.258 | −6.25 | 0.695 | −26.06 | 8.459 | −9.22 | 4.774 | 10.33 |
3-methyl-PCB-44 | 6.991 | 14.3 | 4.036 | −11.14 | 0.704 | −25.11 | 8.201 | −11.99 | 4.153 | −4.02 |
3-ethyl-PCB-44 | 7.200 | 11.7 | 4.040 | −11.05 | 0.709 | −24.57 | 8.291 | −11.02 | 4.423 | 2.22 |
3-isopropyl-PCB-44 | 7.353 | 9.9 | 4.143 | −8.78 | 0.710 | −24.47 | 8.370 | −10.17 | 4.401 | 1.71 |
5′-carboxyl-PCB-44 | 5.260 | 35.5 | 4.817 | 6.05 | 1.075 | 14.36 | 9.770 | 4.85 | 3.243 | −25.05 |
5′-amino-PCB-44 | 6.459 | 20.8 | 3.757 | −17.28 | 0.546 | −41.91 | 7.990 | −14.25 | 4.641 | 7.26 |
5′-hydroxyl-PCB-44 | 7.637 | 6.4 | 4.367 | −3.85 | 0.832 | −11.49 | 8.863 | −4.88 | 4.754 | 9.87 |
5′-vinyl-PCB-44 | 5.881 | 27.9 | 4.354 | −4.14 | 0.740 | −21.28 | 8.667 | −6.99 | 4.688 | 8.34 |
5′-methyl-PCB-44 | 6.957 | 14.7 | 4.936 | 8.67 | 1.206 | 28.30 | 9.181 | −1.47 | 5.171 | 19.51 |
5′-ethyl-PCB-44 | 6.616 | 18.9 | 4.230 | −6.87 | 0.601 | −36.06 | 8.030 | −13.82 | 4.728 | 9.27 |
5′-isopropyl-PCB-44 | 6.094 | 25.3 | 4.169 | −8.21 | 0.667 | −29.04 | 8.321 | −10.70 | 4.657 | 7.63 |
5′-tert-butyl-PCB-44 | 5.000 | 38.7 | 4.998 | 10.04 | 1.046 | 11.28 | 9.826 | 5.45 | 5.235 | 20.98 |
3-Br-5′-aldehyde-PCB-44 | 6.838 | 16.2 | 4.845 | 6.67 | 1.177 | 25.21 | 9.096 | −2.38 | 5.171 | 19.51 |
3-Br-5′-amino-PCB-44 | 7.057 | 13.5 | 4.314 | −5.02 | 0.819 | −12.87 | 8.790 | −5.67 | 4.869 | 12.53 |
3-Br-5′-hydroxyl-PCB-44 | 7.581 | 7.1 | 4.310 | −5.11 | 0.796 | −15.32 | 8.758 | −6.01 | 4.752 | 9.82 |
3-methoxy-5′-aldehyde-PCB-44 | 5.698 | 30.2 | 5.563 | 22.48 | 0.901 | −4.15 | 9.292 | −0.28 | 3.186 | −26.37 |
3-methoxy-5′-carboxyl-PCB-44 | 5.690 | 30.3 | 5.483 | 20.72 | 0.969 | 3.09 | 9.623 | 3.27 | 4.043 | −6.56 |
3-methoxy-5′-amino-PCB-44 | 6.665 | 18.3 | 2.559 | −43.66 | 0.458 | −51.28 | 7.816 | −16.12 | 5.187 | 19.88 |
3-methoxy-5′-hydroxyl-PCB-44 | 5.682 | 30.4 | 4.727 | 4.07 | 0.743 | −20.96 | 8.813 | −5.42 | 3.999 | −7.58 |
3-ethinyl-5′-aldehyde-PCB-44 | 5.676 | 30.4 | 5.220 | 14.93 | 0.939 | −0.11 | 9.188 | −1.40 | 2.945 | −31.94 |
3-ethinyl-5′-carboxyl-PCB-44 | 5.669 | 30.5 | 5.133 | 13.01 | 1.007 | 7.13 | 9.518 | 2.15 | 3.795 | −12.29 |
3-ethinyl-5′-amino-PCB-44 | 6.503 | 20.3 | 3.652 | −19.59 | 0.494 | −47.45 | 7.863 | −15.61 | 4.595 | 6.19 |
3-ethinyl-5′-hydroxyl-PCB-44 | 6.084 | 25.4 | 2.715 | −40.22 | 0.840 | −10.64 | 7.970 | −14.47 | 4.424 | 2.24 |
3-vinyl-5′-aldehyde-PCB-44 | 7.783 | 4.6 | 4.818 | 6.08 | 0.960 | 2.13 | 8.803 | −5.53 | 4.606 | 6.45 |
3-vinyl-5′-carboxyl-PCB-44 | 5.290 | 35.2 | 4.929 | 8.52 | 0.877 | −6.70 | 8.983 | −3.60 | 3.901 | −9.85 |
3-vinyl-5′-amino-PCB-44 | 5.629 | 31 | 2.585 | −43.09 | 0.548 | −41.70 | 6.910 | −25.84 | 4.070 | −5.94 |
3-vinyl-5′-hydroxyl-PCB-44 | 7.167 | 12.1 | 3.911 | −13.89 | 0.667 | −29.04 | 8.265 | −11.30 | 4.596 | 6.22 |
3-methyl-5′-aldehyde-PCB-44 | 6.950 | 14.7 | 4.755 | 4.69 | 0.889 | −5.43 | 8.277 | −11.17 | 4.576 | 5.75 |
3-methyl-5′-carboxyl-PCB-44 | 7.714 | 5.4 | 4.801 | 5.70 | 1.006 | 7.02 | 8.819 | −5.36 | 3.853 | −10.95 |
3-methyl-5′-amino-PCB-44 | 6.202 | 24 | 2.687 | −40.84 | 0.441 | −53.09 | 6.455 | −30.73 | 4.017 | −7.16 |
3-methyl-5′-hydroxyl-PCB-44 | 6.343 | 22.2 | 3.859 | −15.04 | 0.596 | −36.60 | 7.747 | −16.86 | 4.584 | 5.94 |
3-ethyl-5′-aldehyde-PCB-44 | 7.135 | 12.5 | 4.993 | 9.93 | 0.893 | −5.00 | 8.378 | −10.09 | 4.750 | 9.78 |
3-ethyl-5′-carboxyl-PCB-44 | 7.893 | 3.2 | 5.041 | 10.99 | 1.010 | 7.45 | 8.918 | −4.29 | 4.026 | −6.96 |
3-ethyl-5′-amino-PCB-44 | 5.341 | 34.5 | 3.491 | −23.14 | 0.313 | −66.70 | 6.967 | −25.23 | 4.625 | 6.89 |
3-ethyl-5′-hydroxyl-PCB-44 | 6.524 | 20 | 4.090 | −9.95 | 0.600 | −36.17 | 7.844 | −15.82 | 4.749 | 9.75 |
3-isopropyl-5′-aldehyde-PCB-44 | 7.272 | 10.9 | 4.754 | 4.67 | 0.894 | −4.89 | 8.421 | −9.63 | 4.683 | 8.23 |
3-isopropyl-5′-carboxyl-PCB-44 | 8.034 | 1.5 | 4.804 | 5.77 | 1.011 | 7.55 | 8.962 | −3.82 | 3.960 | −8.48 |
3-isopropyl-5′-amino-PCB-44 | 5.917 | 27.5 | 2.615 | −42.43 | 0.454 | −51.70 | 6.559 | −29.61 | 4.098 | −5.29 |
3-isopropyl-5′-hydroxyl-PCB-44 | 6.665 | 18.3 | 3.865 | −14.91 | 0.601 | −36.06 | 7.889 | −15.34 | 4.684 | 8.25 |
3-tert-butyl-5′-amino-PCB-44 | 7.539 | 7.6 | 4.409 | −2.93 | 0.617 | −34.36 | 8.620 | −7.49 | 5.426 | 25.40 |
3-Br-5′-Br-PCB-44 | 8.106 | 0.6 | 4.406 | −2.99 | 0.863 | −8.19 | 9.081 | −2.54 | 4.347 | 0.46 |
3-carboxyl-5′-carboxyl-PCB-44 | 5.726 | 29.8 | 5.193 | 14.33 | 1.277 | 35.85 | 10.435 | 11.99 | 2.538 | −41.35 |
3-amino-5′-amino-PCB-44 | 5.182 | 36.5 | 3.276 | −27.87 | 0.300 | −68.09 | 6.882 | −26.14 | 4.246 | −1.87 |
3-hydroxyl-5′-hydroxyl-PCB-44 | 5.809 | 28.8 | 4.255 | -6.32 | 0.762 | −18.94 | 8.407 | −9.78 | 3.549 | −17.98 |
3-vinyl-5′-vinyl-PCB-44 | 5.333 | 34.6 | 4.032 | −11.23 | 0.570 | −39.36 | 7.996 | −14.19 | 4.543 | 4.99 |
3-methyl-5′-methyl-PCB-44 | 5.131 | 37.1 | 3.440 | −24.26 | 0.346 | −63.19 | 6.804 | −26.98 | 4.406 | 1.83 |
3-ethyl-5′-ethyl-PCB-44 | 5.530 | 32.2 | 3.544 | −21.97 | 0.370 | −60.64 | 7.003 | −24.84 | 4.801 | 10.95 |
3-isopropyl-5′-isopropyl-PCB-44 | 5.834 | 28.5 | 4.542 | 0.00 | 0.394 | −58.09 | 7.194 | −22.79 | 4.327 | 0.00 |
Compounds | 2AYR | 2Q70 | 1ERR | 2Q6J | 2IOK | |||||
---|---|---|---|---|---|---|---|---|---|---|
Docking Score | Change Rate (%) | Docking Score | Change Rate (%) | Docking Score | Change Rate (%) | Docking Score | Change Rate (%) | Docking Score | Change Rate (%) | |
Target molecule PCB-44 | 3.06 | 3.40 | 4.28 | 2.94 | 2.90 | |||||
3-amino-PCB-44 | 2.74 | −10.46 | 3.57 | 5.00 | 3.67 | −14.25 | 3.41 | 16.10 | 3.49 | 20.39 |
3-methyl-PCB-44 | 4.22 | 37.91 | 3.28 | −3.53 | 4.35 | 1.64 | 2.57 | −12.61 | 2.82 | −2.84 |
3-vinyl-5′-amino-PCB-44 | 5.05 | 65.03 | 5.86 | 72.35 | 4.30 | 0.47 | 3.22 | 9.74 | 4.29 | 47.88 |
3-methyl-5′-amino-PCB-44 | 4.23 | 38.24 | 5.20 | 52.94 | 5.84 | 36.45 | 3.63 | 23.70 | 4.76 | 64.34 |
3-isopropyl-5′-amino-PCB-44 | 5.11 | 66.99 | 5.78 | 70.00 | 4.38 | 2.34 | 4.04 | 37.45 | 4.81 | 65.93 |
3-amino-5′-amino-PCB-44 | 4.39 | 43.46 | 5.54 | 62.94 | 3.50 | −18.22 | 4.03 | 37.13 | 5.43 | 87.41 |
3-hydroxyl-5′-hydroxyl-PCB-44 | 4.10 | 33.99 | 4.38 | 28.82 | 4.95 | 15.65 | 4.45 | 51.48 | 4.59 | 58.43 |
Before Modification | After Modification | |||||||
---|---|---|---|---|---|---|---|---|
Name of Amino Acid Residue | Target Molecule PCB-44 | 3-methyl-PCB-44 | 3-amino-PCB-44 | 3-hydroxyl-5′-hydroxyl-PCB-44 | 3-vinyl-5′-amino-PCB-44 | 3-methyl-5′-amino-PCB-44 | 3-isopropyl-5′-amino-PCB-44 | 3-amino-5′-amino-PCB-44 |
Docking score | 2.94 | 2.57 | 3.41 | 4.45 | 3.22 | 3.63 | 4.04 | 4.03 |
Hydrophobic residues | Leu346 | 3.5 | 3.7 | 5.6 | 3.9 | 5.2 | 4.3 | 3.5 |
Ale350 | 5.7 | 4.1 | 4.0 | 4.7 | 4.2 | 3.7 | 3.8 | |
Leu387 | 5.1 | - | 4.6 | 5.3 | 5.0 | 4.8 | 3.8 | |
Met388 | 6.6 | - | 5.8 | 7.1 | 5.9 | 7.6 | 5.0 | |
Phe404 | 3.1 | - | 4.6 | 4.0 | 6.0 | 4.6 | 3.6 | |
Met421 | 7.4 | 4.8 | 4.3 | 5.7 | 3.8 | 5.4 | 6.9 | |
Average distance (Å) | 5.23 | 4.20 | 4.82 | 5.12 | 5.02 | 5.07 | 4.43 | 5.00 |
Hydrophilic residues | Thr347 | - | 3.5 | - | - | - | - | - |
Glu353 | - | - | 3.9 | 3.9 | 4.0 | 3.9 | 4.1 | |
His524 | - | - | - | - | - | - | - |
Combinations | A (mmol/L) | B (mmol/L) | C (mmol/L) | D (mmol/L) |
---|---|---|---|---|
1 | 0 | 0 | 0 | 0 |
2 | 0 | 0.96 | 0.94 | 0.96 |
3 | 0 | 1.92 | 1.88 | 1.92 |
4 | 0.95 | 0 | 0.94 | 1.92 |
5 | 0.95 | 0.96 | 1.88 | 0 |
6 | 0.95 | 1.92 | 0 | 0.96 |
7 | 1.90 | 0 | 0.94 | 0.96 |
8 | 1.90 | 0.96 | 0 | 1.92 |
9 | 1.90 | 1.92 | 1.88 | 0 |
PCB-44 | 3-methyl-PCB-44 | 3-amino-PCB-44 | 3-hydroxyl-5′-hydroxyl-PCB-44 | 3-vinyl-5′-amino-PCB-44 | 3-methyl-5′-amino-PCB-44 | 3-isopropyl-5′-amino-PCB-44 | 3-amino-5′-amino-PCB-44 | |
---|---|---|---|---|---|---|---|---|
Combination 1 | −136.317 | −133.293 | −138.483 | −128.696 | −135.967 | −140.651 | −102.431 | −105.153 |
Change rate (%) | −2.22 | 1.59 | −5.59 | −0.26 | 3.18 | −24.86 | −22.86 | |
Combination 2 | −145.044 | −139.843 | −107.763 | −115.925 | −128.898 | −129.797 | −104.278 | −99.087 |
Change rate (%) | −3.59 | −25.7 | −20.08 | −11.13 | −10.51 | −28.11 | −31.68 | |
Combination 3 | −140.755 | −134.72 | −131.681 | −127.886 | −124.711 | −151.602 | −93.373 | −97.705 |
Change rate (%) | −4.29 | −6.45 | −9.14 | −11.4 | 7.71 | −33.66 | −30.59 | |
Combination 4 | −128.654 | −135.583 | −136.997 | −112.013 | −132.642 | −136.842 | −87.189 | −89.155 |
Change rate (%) | 5.39 | 6.48 | −12.93 | 3.1 | 6.36 | −32.23 | −30.7 | |
Combination 5 | −124.468 | −126.849 | −129.241 | −124.585 | −121.917 | −133.491 | −98.075 | −99.583 |
Change rate (%) | 1.91 | 3.83 | 0.09 | −2.05 | 7.25 | −21.2 | −19.99 | |
Combination 6 | −125.964 | −137.308 | −119.652 | −129.574 | −131.267 | −140.547 | −94.746 | −94.105 |
Change rate (%) | 9.01 | −5.01 | 2.87 | 4.21 | 11.58 | −24.78 | −25.29 | |
Combination 7 | −142.61 | −127.914 | −120.375 | −116.144 | −129.26 | −137.648 | −103.637 | −101.748 |
Change rate (%) | −10.31 | −15.59 | −18.56 | −9.36 | −3.48 | −27.33 | −28.65 | |
Combination 8 | −136.574 | −127.681 | −119.583 | −126.673 | −106.3 | −126.598 | −99.966 | −105.671 |
Change rate (%) | −6.51 | −12.44 | −7.25 | −22.17 | −7.3 | −26.8 | −22.63 | |
Combination 9 | −131.23 | −107.546 | −126.97 | −123.287 | −132.44 | −138.777 | −113.162 | −100.038 |
Change rate (%) | −18.05 | −3.25 | −6.05 | 0.92 | 5.75 | −13.77 | −23.77 |
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He, W.; Zhang, W.; Chu, Z.; Li, Y. Mitigating the Adverse Effects of Polychlorinated Biphenyl Derivatives on Estrogenic Activity via Molecular Modification Techniques. Int. J. Environ. Res. Public Health 2021, 18, 4999. https://doi.org/10.3390/ijerph18094999
He W, Zhang W, Chu Z, Li Y. Mitigating the Adverse Effects of Polychlorinated Biphenyl Derivatives on Estrogenic Activity via Molecular Modification Techniques. International Journal of Environmental Research and Public Health. 2021; 18(9):4999. https://doi.org/10.3390/ijerph18094999
Chicago/Turabian StyleHe, Wei, Wenhui Zhang, Zhenhua Chu, and Yu Li. 2021. "Mitigating the Adverse Effects of Polychlorinated Biphenyl Derivatives on Estrogenic Activity via Molecular Modification Techniques" International Journal of Environmental Research and Public Health 18, no. 9: 4999. https://doi.org/10.3390/ijerph18094999