A Toxicity Prediction Tool for Potential Agonist/Antagonist Activities in Molecular Initiating Events Based on Chemical Structures
Abstract
:1. Introduction
2. Results and Discussion
2.1. Distributions of Active and Inactive Compounds
2.2. Models and Performances
2.3. Comparison with the Tox21 Data Challenge 2014
2.4. Implementation of the Models in the Toxicity Predictor
3. Materials and Methods
3.1. Biological Overview of Modeled MIEs
3.2. Data Source
3.3. qHTS Data Analysis
3.4. Conformations and Descriptors
3.5. ML Algorithm and Modeling Scheme
3.6. Evaluation Metrics
- (1)
- SE: accuracy of predicting “positive” (active) when the true outcome is positive.
- (2)
- SP: accuracy of predicting “negative” (inactive) when the true outcome is negative.
- (3)
- ACC: the number of correctly predicted samples divided by the total number of samples.
- (4)
- BAC: average between SE and SP.
- (5)
- MCC: used as a measure to assess the classification accuracy of the models for an unbalanced dataset [71].
- (6)
- AUC: a graph showing the performance of a classification model at all classification thresholds. This curve plots two parameters: (i) SE and (ii) 1–SP [72].
3.7. Applicability Domain
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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No. | AID | Abbreviation | Criteria 40 | Criteria 1 | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
AUC | SE | SP | ACC | BAC | MCC | AUC | SE | SP | ACC | BAC | MCC | |||
1 | 720516 | ATAD5_ind | 0.840 | 0.750 | 0.843 | 0.840 | 0.796 | 0.272 | 0.845 | 0.744 | 0.847 | 0.839 | 0.795 | 0.395 |
2 | 720552 | p53_ago | 0.899 | 0.824 | 0.830 | 0.830 | 0.827 | 0.356 | 0.845 | 0.804 | 0.793 | 0.794 | 0.799 | 0.458 |
3 | 720637 | MMP_disr | 0.919 | 0.845 | 0.846 | 0.846 | 0.845 | 0.501 | 0.795 | 0.698 | 0.788 | 0.758 | 0.743 | 0.475 |
4 | 720719 | GR_ago | 0.783 | 0.600 | 0.931 | 0.923 | 0.766 | 0.300 | 0.841 | 0.754 | 0.807 | 0.800 | 0.780 | 0.416 |
5 | 720725 | GR_ant | 0.808 | 0.577 | 0.905 | 0.888 | 0.741 | 0.328 | 0.827 | 0.801 | 0.721 | 0.743 | 0.761 | 0.471 |
6 | 743053 | Arlbd_ago | 0.878 | 0.765 | 0.947 | 0.941 | 0.856 | 0.481 | 0.766 | 0.582 | 0.843 | 0.806 | 0.712 | 0.357 |
7 | 743054 | ARfull_ant | 0.774 | 0.750 | 0.681 | 0.683 | 0.716 | 0.169 | 0.833 | 0.841 | 0.700 | 0.734 | 0.770 | 0.468 |
8 | 743063 | Arlbd_ant | 0.844 | 0.786 | 0.791 | 0.790 | 0.788 | 0.338 | 0.833 | 0.805 | 0.724 | 0.745 | 0.765 | 0.469 |
9 | 743067 | TR_ant | 0.783 | 0.511 | 0.924 | 0.906 | 0.718 | 0.306 | 0.829 | 0.740 | 0.825 | 0.796 | 0.782 | 0.555 |
10 | 743077 | ERlbd_ago | 0.782 | 0.536 | 0.961 | 0.938 | 0.748 | 0.457 | 0.735 | 0.600 | 0.843 | 0.812 | 0.722 | 0.362 |
11 | 743078 | ERlbd_ant | 0.810 | 0.815 | 0.684 | 0.691 | 0.750 | 0.237 | 0.805 | 0.696 | 0.789 | 0.767 | 0.743 | 0.444 |
12 | 743091 | ERfull_ant | 0.826 | 0.872 | 0.699 | 0.705 | 0.785 | 0.235 | 0.862 | 0.730 | 0.870 | 0.842 | 0.800 | 0.555 |
13 | 743122 | AhR_ago | 0.888 | 0.713 | 0.907 | 0.887 | 0.810 | 0.513 | 0.749 | 0.728 | 0.695 | 0.702 | 0.711 | 0.359 |
14 | 743139 | Arom_ant | 0.801 | 0.892 | 0.598 | 0.608 | 0.745 | 0.186 | 0.807 | 0.825 | 0.661 | 0.704 | 0.743 | 0.429 |
15 | 743140 | PPARg_ago | 0.813 | 0.750 | 0.823 | 0.821 | 0.786 | 0.238 | 0.832 | 0.735 | 0.819 | 0.805 | 0.777 | 0.457 |
16 | 743199 | PPARg_ant | 0.829 | 0.786 | 0.798 | 0.798 | 0.792 | 0.290 | 0.810 | 0.824 | 0.645 | 0.682 | 0.734 | 0.383 |
17 | 743219 | ARE_ago | 0.785 | 0.794 | 0.652 | 0.672 | 0.723 | 0.317 | 0.795 | 0.770 | 0.715 | 0.733 | 0.742 | 0.461 |
18 | 743226 | PPARd_ant | 0.681 | 0.600 | 0.885 | 0.884 | 0.743 | 0.111 | 0.811 | 0.764 | 0.749 | 0.751 | 0.756 | 0.374 |
19 | 743227 | PPARd_ago | 0.812 | 0.615 | 0.954 | 0.949 | 0.785 | 0.296 | 0.796 | 0.705 | 0.790 | 0.780 | 0.747 | 0.356 |
20 | 743228 | HSR_act | 0.788 | 0.576 | 0.922 | 0.910 | 0.749 | 0.315 | 0.790 | 0.667 | 0.808 | 0.789 | 0.737 | 0.370 |
21 | 743239 | FXR_ago | 0.775 | 0.727 | 0.836 | 0.835 | 0.782 | 0.163 | 0.817 | 0.689 | 0.834 | 0.825 | 0.762 | 0.325 |
22 | 743240 | FXR_ant | 0.757 | 0.933 | 0.565 | 0.577 | 0.749 | 0.178 | 0.843 | 0.788 | 0.799 | 0.798 | 0.794 | 0.481 |
23 | 743241 | VDR_ago | N.D | N.D | N.D | N.D | N.D | N.D | 0.826 | 0.769 | 0.727 | 0.730 | 0.748 | 0.297 |
24 | 743242 | VDR_ant | 0.716 | 1.000 | 0.399 | 0.403 | 0.699 | 0.066 | 0.701 | 0.630 | 0.689 | 0.678 | 0.660 | 0.258 |
25 | 1159518 | NFkB_ago | 0.780 | 0.667 | 0.846 | 0.846 | 0.756 | 0.081 | 0.871 | 0.692 | 0.912 | 0.900 | 0.802 | 0.427 |
26 | 1159519 | ERsr_ago | 0.638 | 0.857 | 0.441 | 0.445 | 0.649 | 0.052 | 0.801 | 0.655 | 0.833 | 0.816 | 0.744 | 0.349 |
27 | 1159523 | ROR_ant | 0.828 | 0.789 | 0.764 | 0.766 | 0.777 | 0.323 | 0.695 | 0.523 | 0.819 | 0.703 | 0.671 | 0.359 |
28 | 1159528 | AP1_ago | 0.777 | 0.553 | 0.877 | 0.851 | 0.715 | 0.319 | 0.799 | 0.765 | 0.722 | 0.729 | 0.743 | 0.372 |
29 | 1159531 | RXR_ago | 0.532 | 0.235 | 0.964 | 0.951 | 0.600 | 0.135 | 0.725 | 0.527 | 0.841 | 0.756 | 0.684 | 0.374 |
30 | 1159555 | RAR_ant | 0.831 | 0.800 | 0.742 | 0.746 | 0.771 | 0.308 | 0.683 | 0.740 | 0.511 | 0.601 | 0.626 | 0.249 |
31 | 1224892 | CAR_ago | 0.889 | 0.826 | 0.808 | 0.810 | 0.817 | 0.455 | 0.847 | 0.684 | 0.889 | 0.845 | 0.787 | 0.556 |
32 | 1224893 | CAR_ant | 0.809 | 0.652 | 0.880 | 0.874 | 0.766 | 0.239 | 0.793 | 0.700 | 0.768 | 0.746 | 0.734 | 0.448 |
33 | 1224894 | HIF1_ago | 0.556 | 0.250 | 1.000 | 0.997 | 0.625 | 0.499 | 0.854 | 0.769 | 0.829 | 0.824 | 0.799 | 0.395 |
34 | 1224895 | TSHR_ago | 0.872 | 0.750 | 0.880 | 0.874 | 0.815 | 0.355 | 0.838 | 0.692 | 0.831 | 0.816 | 0.762 | 0.389 |
35 | 1224896 | H2AX_ago | 0.834 | 0.696 | 0.892 | 0.880 | 0.794 | 0.394 | 0.779 | 0.605 | 0.842 | 0.814 | 0.724 | 0.354 |
36 | 1259247 | Arfulls_ant | 0.856 | 0.857 | 0.733 | 0.747 | 0.795 | 0.401 | 0.824 | 0.788 | 0.767 | 0.774 | 0.778 | 0.534 |
37 | 1259248 | Erfulls_ant | 0.835 | 0.850 | 0.702 | 0.711 | 0.776 | 0.283 | 0.793 | 0.668 | 0.798 | 0.770 | 0.733 | 0.416 |
38 | 1259387 | ARant_ago | 0.852 | 0.727 | 0.946 | 0.939 | 0.837 | 0.460 | 0.712 | 0.494 | 0.872 | 0.841 | 0.683 | 0.275 |
39 | 1259388 | HDAC_ant | 0.897 | 0.783 | 0.888 | 0.883 | 0.835 | 0.407 | 0.868 | 0.768 | 0.879 | 0.871 | 0.824 | 0.447 |
40 | 1259390 | Shh_ago | 0.571 | 1.000 | 0.219 | 0.223 | 0.609 | 0.042 | 0.724 | 0.609 | 0.913 | 0.905 | 0.761 | 0.266 |
41 | 1259391 | ERaant_ago | 0.934 | 0.850 | 0.959 | 0.956 | 0.904 | 0.493 | 0.782 | 0.551 | 0.898 | 0.880 | 0.725 | 0.299 |
42 | 1259392 | Shh_ant | 0.829 | 0.809 | 0.718 | 0.731 | 0.764 | 0.379 | 0.758 | 0.642 | 0.745 | 0.705 | 0.693 | 0.383 |
43 | 1259393 | TSHR_agoant | 0.834 | 0.750 | 0.875 | 0.874 | 0.812 | 0.120 | 0.669 | 0.727 | 0.681 | 0.682 | 0.704 | 0.093 |
44 | 1259394 | ERb_ago | 0.980 | 0.923 | 0.973 | 0.972 | 0.948 | 0.531 | 0.729 | 0.444 | 0.937 | 0.900 | 0.691 | 0.348 |
45 | 1259395 | TSHR_ant | 0.865 | 0.933 | 0.715 | 0.721 | 0.824 | 0.244 | 0.850 | 0.800 | 0.807 | 0.807 | 0.804 | 0.381 |
46 | 1259396 | Erb_ant | 0.825 | 0.677 | 0.863 | 0.851 | 0.770 | 0.352 | 0.798 | 0.743 | 0.763 | 0.758 | 0.753 | 0.462 |
47 | 1259401 | ERRPGC_ant | 0.843 | 0.698 | 0.843 | 0.837 | 0.770 | 0.290 | 0.751 | 0.595 | 0.793 | 0.723 | 0.694 | 0.390 |
48 | 1259402 | ERRPGC_ago | 0.840 | 0.650 | 0.937 | 0.925 | 0.794 | 0.415 | 0.805 | 0.734 | 0.777 | 0.768 | 0.756 | 0.444 |
49 | 1259403 | ERR_ant | 0.812 | 0.653 | 0.856 | 0.835 | 0.755 | 0.392 | 0.819 | 0.696 | 0.826 | 0.786 | 0.761 | 0.510 |
50 | 1259404 | ERR_ago | 0.884 | 0.880 | 0.814 | 0.816 | 0.847 | 0.274 | 0.803 | 0.680 | 0.820 | 0.777 | 0.750 | 0.491 |
51 | 1347030 | TRHR_ago | 0.748 | 0.833 | 0.637 | 0.638 | 0.735 | 0.077 | 0.751 | 0.593 | 0.853 | 0.846 | 0.723 | 0.201 |
52 | 1347031 | PR_ant | 0.892 | 0.880 | 0.794 | 0.804 | 0.837 | 0.473 | 0.831 | 0.757 | 0.821 | 0.802 | 0.789 | 0.550 |
53 | 1347032 | TGFb_ant | 0.809 | 0.750 | 0.765 | 0.764 | 0.757 | 0.273 | 0.860 | 0.780 | 0.824 | 0.817 | 0.802 | 0.493 |
54 | 1347033 | PXR_ago | 0.851 | 0.759 | 0.817 | 0.805 | 0.788 | 0.517 | 0.838 | 0.745 | 0.817 | 0.790 | 0.781 | 0.556 |
55 | 1347034 | CaspH_ind | 0.870 | 0.791 | 0.852 | 0.849 | 0.821 | 0.348 | 0.858 | 0.773 | 0.856 | 0.848 | 0.814 | 0.452 |
56 | 1347035 | TGFb_ago | 0.968 | 1.000 | 0.938 | 0.938 | 0.969 | 0.174 | 0.900 | 0.818 | 0.937 | 0.936 | 0.878 | 0.311 |
57 | 1347036 | PR_ago | 0.943 | 0.833 | 0.989 | 0.986 | 0.911 | 0.701 | 0.799 | 0.537 | 0.986 | 0.967 | 0.761 | 0.564 |
58 | 1347037 | CaspC_ind | 0.884 | 0.850 | 0.785 | 0.786 | 0.817 | 0.216 | 0.863 | 0.771 | 0.882 | 0.878 | 0.827 | 0.351 |
59 | 1347038 | TRHR_ant | 0.822 | 0.700 | 0.841 | 0.840 | 0.771 | 0.148 | 0.828 | 0.870 | 0.701 | 0.709 | 0.785 | 0.260 |
Metrics | Criteria 40 | Criteria 1 |
---|---|---|
AUC | 0.817 ± 0.088 | 0.802 ± 0.051 |
SE | 0.750 ± 0.151 | 0.705 ± 0.094 |
SP | 0.809 ± 0.149 | 0.801 ± 0.082 |
ACC | 0.807 ± 0.144 | 0.788 ± 0.069 |
BAC | 0.780 ± 0.069 | 0.753 ± 0.045 |
MCC | 0.307 ± 0.141 | 0.402 ± 0.096 |
No. | AID | Molecular Initiating Events | Activity Type | Abbreviation |
---|---|---|---|---|
1 | 720516 | ATAD5 | genotoxic inducer | ATAD5_ind |
2 | 720552 | p53 | agonist | p53_ago |
3 | 720637 | mitochondrial membrane potential | disruptor | MMP_disr |
4 | 720719 | glucocorticoid receptor | agonist | GR_ago |
5 | 720725 | glucocorticoid receptor | antagonist | GR_ant |
6 | 743053 | androgen receptor lbd | agonist | Arlbd_ago |
7 | 743054 | androgen receptor full | antagonist | ARfull_ant |
8 | 743063 | androgen receptor lbd | antagonist | Arlbd_ant |
9 | 743067 | thyroid receptor | antagonist | TR_ant |
10 | 743077 | estrogen receptor alpha lbd | agonist | ERlbd_ago |
11 | 743078 | estrogen receptor alpha lbd | antagonist | ERlbd_ant |
12 | 743091 | estrogen receptor alpha full | antagonist | ERfull_ant |
13 | 743122 | aryl hydrocarbon receptor | agonist | AhR_ago |
14 | 743139 | aromatase | antagonist | Arom_ant |
15 | 743140 | peroxisome proliferator-activated receptor gamma | agonist | PPARg_ago |
16 | 743199 | peroxisome proliferator-activated receptor gamma | antagonist | PPARg_ant |
17 | 743219 | antioxidant response element | agonist | ARE_ago |
18 | 743226 | peroxisome proliferator-activated receptor delta | antagonist | PPARd_ant |
19 | 743227 | peroxisome proliferator-activated receptor delta | agonist | PPARd_ago |
20 | 743228 | heat shock response | activator | HSR_act |
21 | 743239 | farnesoid-X-receptor | agonist | FXR_ago |
22 | 743240 | farnesoid-X-receptor | antagonist | FXR_ant |
23 | 743241 | vitamin D receptor | agonist | VDR_ago |
24 | 743242 | vitamin D receptor | antagonist | VDR_ant |
25 | 1159518 | NFkB | agonist | NFkB_ago |
26 | 1159519 | endoplasmic reticulum stress response | agonist | ERsr_ago |
27 | 1159523 | retinoid-related orphan receptor gamma | antagonist | ROR_ant |
28 | 1159528 | activator protein-1 | agonist | AP1_ago |
29 | 1159531 | retinoid X receptor-alpha | agonist | RXR_ago |
30 | 1159555 | retinoic acid receptor | antagonist | RAR_ant |
31 | 1224892 | constitutive androstane receptor | agonist | CAR_ago |
32 | 1224893 | constitutive androstane receptor | antagonist | CAR_ant |
33 | 1224894 | hypoxia | agonist | HIF1_ago |
34 | 1224895 | thyroid stimulating hormone receptor | agonist | TSHR_ago |
35 | 1224896 | histone variant H2AX | agonist | H2AX_ago |
36 | 1259247 | androgen receptor with stimulator | antagonist | Arfulls_ant |
37 | 1259248 | estrogen receptor alpha with stimulator | antagonist | Erfulls_ant |
38 | 1259387 | androgen receptor with antagonist | agonist | ARant_ago |
39 | 1259388 | histone deacetylase | antagonist | HDAC_ant |
40 | 1259390 | sonic hedgehog signaling | agonist | Shh_ago |
41 | 1259391 | estrogen receptor alpha with antagonist | agonist | ERaant_ago |
42 | 1259392 | sonic hedgehog signaling | antagonist | Shh_ant |
43 | 1259393 | thyroid stimulating hormone receptor | agonist antagonist | TSHR_agoant |
44 | 1259394 | estrogen receptor beta | agonist | ERb_ago |
45 | 1259395 | thyroid stimulating hormone receptor | antagonist | TSHR_ant |
46 | 1259396 | estrogen receptor beta | antagonist | Erb_ant |
47 | 1259401 | estrogen related receptor with PGC | antagonist | ERRPGC_ant |
48 | 1259402 | estrogen related receptor with PGC | agonist | ERRPGC_ago |
49 | 1259403 | estrogen related receptor | antagonist | ERR_ant |
50 | 1259404 | estrogen related receptor | agonist | ERR_ago |
51 | 1347030 | thyrotropin releasing hormone receptor | agonist | TRHR_ago |
52 | 1347031 | progesterone receptor | antagonist | PR_ant |
53 | 1347032 | transforming growth factor beta | antagonist | TGFb_ant |
54 | 1347033 | human pregnane X receptor | agonist | PXR_ago |
55 | 1347034 | caspase-3/7 in HepG2 | inducer | CaspH_ind |
56 | 1347035 | transforming growth factor beta | agonist | TGFb_ago |
57 | 1347036 | progesterone receptor | agonist | PR_ago |
58 | 1347037 | caspase-3/7 in CHO-K1 | inducer | CaspC_ind |
59 | 1347038 | thyrotropin releasing hormone receptor | antagonist | TRHR_ant |
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Kurosaki, K.; Wu, R.; Uesawa, Y. A Toxicity Prediction Tool for Potential Agonist/Antagonist Activities in Molecular Initiating Events Based on Chemical Structures. Int. J. Mol. Sci. 2020, 21, 7853. https://doi.org/10.3390/ijms21217853
Kurosaki K, Wu R, Uesawa Y. A Toxicity Prediction Tool for Potential Agonist/Antagonist Activities in Molecular Initiating Events Based on Chemical Structures. International Journal of Molecular Sciences. 2020; 21(21):7853. https://doi.org/10.3390/ijms21217853
Chicago/Turabian StyleKurosaki, Kota, Raymond Wu, and Yoshihiro Uesawa. 2020. "A Toxicity Prediction Tool for Potential Agonist/Antagonist Activities in Molecular Initiating Events Based on Chemical Structures" International Journal of Molecular Sciences 21, no. 21: 7853. https://doi.org/10.3390/ijms21217853