Theoretical Studies on the Quantitative Structure–Toxicity Relationship of Polychlorinated Biphenyl Congeners Reveal High Affinity Binding to Multiple Human Nuclear Receptors
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Gathering
2.2. Statistical Methods
2.3. Molecular Docking Simulations
2.4. Molecular Dynamics Simulations
3. Results and Discussion
3.1. Data Gathering
3.2. QSTR Models
- Bioconcentration log10 value (Equation (1));
- D. magna LC50 (48 h) log10 value (Equation (2));
- Fathead minnow LC50 (48 h) log10 value (Equation (3)).
- T. pyriformis IGC50 (48 h) log10 value (Equation (4));
- Fathead minnow LC50 (48 h) value (Equation (5)).
3.3. Molecular Docking
3.4. Molecular Dynamics
- Three of them have extremely favorable (<1 Å) RMSD values;
- Three of them have acceptable (1–3 Å) RMSD values; and
- Two of them have unfavorable (>3 Å) RMSD values.
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Nuclear Receptor | Physiological Function | Dysfunction |
---|---|---|
Estrogen receptor | Bone health maintenance [41] Secondary sex characteristic development Cardiovascular regulation [42] Pregnancy support [43,44] Menstrual cycle support [45,46] | Breast and ovarian cancers [47] |
Progesterone receptor | Breast development [47] Menstrual cycle regulation [48] Pregnancy regulation [49] | Endometriosis and infertility [50] |
Androgen receptor | Facial and body hair growth [51] Muscle development [52] Voice deepening [53] Bone health maintenance [54] | Androgen insensitivity syndrome and prostate cancer [55] |
Vitamin D receptor | Mineral metabolism [56] Immune response regulation [57] Inorganic phosphate homeostasis [58] Calcium homeostasis [59] Bone health maintenance [60] | Autoimmune diseases, cancer, and cardiovascular disorders [61] |
Thyroid hormone receptor | Development regulation [62] Heart regulation [63] Metabolism regulation [64] Lipid metabolism [65] | Thyroid hormone resistance Hypo- and hyperthyroidism [66] |
Retinoic acid receptor | Embryonic development [67] Stem cell differentiation [68] Organ development [67] Vision regulation [69] Immune regulation [70] Skin regulation [71] | Lung and breast cancer [72] Congenital malformations and skin diseases [73] |
Correlated Descriptor | Model | ||
---|---|---|---|
(1) | (2) | (3) | |
Molecular weight | ✓ | ✓ | |
Symmetric atoms | ✓ | ✓ | |
Total surface area | ✓ | ||
Globularity (SVD) | ✓ | ||
Shape index | ✓ | ✓ | |
Molecular flexibility | ✓ | ||
Bend energies | ✓ | ||
Torsion energies | ✓ | ||
Non-1,4 VDW energies | ✓ | ||
Dipole–dipole energies | ✓ | ✓ | |
Synthetic accessibility | ✓ | ✓ | |
correlated descriptors | 6 | 6 | 4 |
Receptor | Ligand | Binding (kcal/mol) | Interactions * | |||||
---|---|---|---|---|---|---|---|---|
HP | HB | H | S | H/HB | E | |||
Estrogen | PCB-129 | −9.319 | 10 | 0 | 0 | 0 | 0 | 0 |
PCB-170 | −9.121 | 11 | 0 | 0 | 0 | 0 | 0 | |
PCB-171 | −9.022 | 8 | 0 | 2 | 0 | 0 | 0 | |
Progesterone | PCB-86 | −8.921 | 8 | 0 | 0 | 0 | 0 | 0 |
PCB-129 | −8.898 | 10 | 0 | 0 | 0 | 0 | 0 | |
PCB-150 | −8.839 | 8 | 0 | 0 | 0 | 0 | 0 | |
Androgen | PCB-157 | −9.121 | 12 | 0 | 1 | 0 | 0 | 0 |
PCB-156 | −9.102 | 11 | 0 | 1 | 0 | 0 | 0 | |
PCB-105 | −8.999 | 14 | 0 | 0 | 0 | 0 | 0 | |
Vitamin D | PCB-126 | −8.802 | 18 | 0 | 0 | 1 | 0 | 0 |
PCB-123 | −8.776 | 13 | 0 | 0 | 0 | 0 | 0 | |
PCB-66 | −8.762 | 12 | 0 | 0 | 0 | 0 | 0 | |
THR-α | PCB-189 | −9.693 | 16 | 1 | 1 | 0 | 0 | 0 |
PCB-156 | −9.620 | 15 | 3 | 0 | 0 | 0 | 0 | |
PCB-106 | −9.342 | 15 | 2 | 0 | 0 | 0 | 0 | |
THR-β | PCB-159 | −9.744 | 17 | 2 | 1 | 1 | 0 | 1 |
PCB-108 | −9.424 | 17 | 2 | 1 | 1 | 0 | 0 | |
PCB-111 | −9.422 | 21 | 2 | 1 | 1 | 0 | 0 | |
RAR-α | PCB-208 | −9.334 | 8 | 1 | 0 | 1 | 0 | 0 |
PCB-199 | −9.220 | 11 | 1 | 0 | 1 | 0 | 0 | |
PCB-198 | −9.097 | 7 | 1 | 0 | 1 | 0 | 0 | |
THR-β | PCB-156 | −10.190 | 17 | 0 | 0 | 0 | 0 | 0 |
PCB-167 | −10.180 | 20 | 0 | 0 | 0 | 0 | 0 | |
PCB-191 | −10.160 | 17 | 0 | 1 | 0 | 1 | 0 |
Receptor | Ligand | RMSD (Å) |
---|---|---|
1A52 Estrogen receptor | Estrogen | 0.867 |
PCB-129 | 1.770 | |
1A28 Progesterone receptor | Progesterone | 0.688 |
PCB-86 | 72.702 | |
1E3G Androgen receptor | Testosterone | 0.822 |
PCB-157 | 1.514 | |
1DB1 Vitamin D receptor | Vitamin D2 | 0.245 |
PCB-126 | 0.949 | |
1NAV Thyroid hormone receptor α | Liothyronine (T3) | 0.750 |
PCB-189 | 0.863 | |
1NAX Thyroid hormone receptor β | Levothyroxine (T4) | 0.366 |
PCB-159 | 0.736 | |
1DKF Retinoic acid receptor α | Alitretinoin | 0.902 |
PCB-208 | 2.076 | |
1XDK Retinoic acid receptor β | Alitretinoin | 0.051 |
PCB-156 | 27.997 |
Receptor | Ligand | Total Interacting Energy (kcal/mol) |
---|---|---|
1A52 Estrogen receptor | Estrogen | 55.576 ± 3.754 |
PCB-129 | 38.714 ± 1.981 | |
1A28 Progesterone receptor | Progesterone | 50.825 ± 3.743 |
PCB-86 | 31.388 ± 2.778 | |
1E3G Androgen receptor | Testosterone | 42.381 ± 1.412 |
PCB-157 | 37.717 ± 2.911 | |
1DB1 Vitamin D receptor | Vitamin D2 | 61.509 ± 3.064 |
PCB-126 | 36.917 ± 1.386 | |
1NAV Thyroid hormone receptor α | Liothyronine (T3) | 64.077 ± 3.703 |
PCB-189 | 49.320 ± 2.681 | |
1NAX Thyroid hormone receptor β | Levothyroxine (T4) | 59.820 ± 4.351 |
PCB-159 | 45.184 ± 1.475 | |
1DKF Retinoic acid receptor α | Alitretinoin | 40.208 ± 2.010 |
PCB-208 | 38.392 ± 2.708 | |
1XDK Retinoic acid receptor β | Alitretinoin | 53.306 ± 3.258 |
PCB-156 | 37.790 ± 2.444 |
Nuclear Receptor | Natural Ligand | PCB | ||
---|---|---|---|---|
Name | Docking Score | Name | Docking Score | |
ER | Estradiol | −10.700 | PCB-129 | −9.319 |
PR | Progesterone | −11.450 | PCB-86 | −8.921 |
AR | Testosterone | −8.289 | PCB-157 | −9.121 |
VDR | Vitamin D2 | −12.220 | PCB-126 | −8.802 |
THRα | T3 | −9.086 | PCB-189 | −9.693 |
THRβ | T3 | −6.649 | PCB-159 | −9.744 |
RARα | Tretinoin | −6.925 | PCB-208 | −9.334 |
RARβ | Tretinoin | −6.925 | PCB-156 | −10.190 |
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Carrera, A.R.M.; Eleazar, E.G.; Caparanga, A.R.; Tayo, L.L. Theoretical Studies on the Quantitative Structure–Toxicity Relationship of Polychlorinated Biphenyl Congeners Reveal High Affinity Binding to Multiple Human Nuclear Receptors. Toxics 2024, 12, 49. https://doi.org/10.3390/toxics12010049
Carrera ARM, Eleazar EG, Caparanga AR, Tayo LL. Theoretical Studies on the Quantitative Structure–Toxicity Relationship of Polychlorinated Biphenyl Congeners Reveal High Affinity Binding to Multiple Human Nuclear Receptors. Toxics. 2024; 12(1):49. https://doi.org/10.3390/toxics12010049
Chicago/Turabian StyleCarrera, Andrei Raphael M., Elisa G. Eleazar, Alvin R. Caparanga, and Lemmuel L. Tayo. 2024. "Theoretical Studies on the Quantitative Structure–Toxicity Relationship of Polychlorinated Biphenyl Congeners Reveal High Affinity Binding to Multiple Human Nuclear Receptors" Toxics 12, no. 1: 49. https://doi.org/10.3390/toxics12010049