Predictive QSAR Models for the Toxicity of Disinfection Byproducts
Abstract
:1. Introduction
2. Materials and Methods
2.1. Experimental Toxicity Data
2.2. Molecular Structure Descriptors
2.3. Data Splits and Model Development
2.4. Model Validation
2.5. Applicability Domain
3. Results and Discussion
3.1. Selected Descriptors
3.2. Models Development and Validation
3.3. Domain of Applicability
3.4. Explanation of Descriptors
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Not available. |
Bioassay | Test Species (Strain/Cell Line) a | Endpoint | Detected Signal |
---|---|---|---|
Microtox | Aliivibrio fischeri | Cytotoxicity | Bioluminescence as indicator for cell viability |
E. coli ± GSH | Escherichia coli MJF335 (GSH−) and MJF276 (GSH+) | Interaction with proteins/peptides | OD at 600 nm as indicator for cell density and descriptor of cell growth |
E. coli ± DNA | Escherichia coli MV4108 (DNA−) and MV1161 (DNA+) | Interaction with DNA | OD at 600 nm as indicator for cell density and descriptor of cell growth |
No. | Name | X-Microtox | GSH+ | GSH− | DNA+ | DNA− | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
Observed pEC50 | Calculated pEC50 | Observed pECIR1.5 | Calculated pECIR1.5 | Observed pECIR1.5 | Calculated pECIR1.5 | Observed pECIR1.5 | Calculated pECIR1.5 | Observed pECIR1.5 | Calculated pECIR1.5 | ||
Halomethanes | |||||||||||
1 | 1,1-dichloroethene | 3.1549 | 3.3214 | 1.3516 | 2.4847 | 1.4145 | 2.4357 | 1.0706 * | 1.7985 * | 0.4318 | 1.6512 |
2 | dichloromethane | 2.2840 | 3.1963 | 1.0888 * | 0.7391 * | 0.8861 | 0.7818 | 0.8539 | 1.6828 | 0.7212 | 0.9997 |
3 | bromochloromethane | 5.0706 | 4.4813 | 1.2182 | 1.6474 | 0.7328 | 1.8741 | 0.6021 | 1.7808 | - | - |
4 | chloroform | 2.4318 | 2.4675 | 1.2366 | 0.9330 | 1.4089 * | 1.0149 * | 1.1675 * | 1.2621 * | 1.0809 | 0.6385 |
5 | bromodichloromethane | 5.0269 | 4.7723 | 1.2111 * | 1.7614 * | 1.4034 | 1.9032 | 1.3188 | 1.6196 | 1.5686 * | 1.2324 * |
6 | bromoform | 3.6383 * | 3.2549 * | 1.0066 | 1.7407 | 1.5850 | 1.9863 | 1.0862 | 1.9166 | 1.1675 | 1.9629 |
7 | dibromochloromethane | 3.0000 * | 3.0193 * | 2.0809 | 1.7617 | 1.9208 | 2.0116 | 1.6990 * | 1.8321 * | 1.5528 * | 1.6647 * |
8 | dichloroiodomethane | 3.4949 * | 3.5960 * | 2.7959 | 2.9585 | 3.2076 | 3.4508 | 2.1938 | 1.8353 | 2.3279 | 1.6163 |
9 | bromochloroiodomethane | 1.6021 | 2.2717 | 2.7959 | 2.8967 | 3.3279 * | 3.3766 * | 2.2291 | 2.9723 | 2.3188 | 1.9777 |
10 | dibromoiodomethane | 4.0506 * | 4.0353 * | 2.8697 * | 2.8209 * | 3.4559 | 3.2854 | 2.0000 * | 1.9755 * | 1.9586 | 2.2126 |
11 | chlorodiiodomethane | 4.6576 | 4.4046 | 3.0809 | 2.9161 | 3.6990 | 3.3999 | 2.4437 * | 2.0457 * | 2.3098 | 2.2495 |
12 | bromodiiodomethane | 5.6021 | 3.8512 | 3.0969 * | 2.8369 * | 3.5850 | 3.3046 | 3.0506 | 1.9836 | 2.9586 * | 2.4210 * |
13 | triiodomethane | 2.4202 | 2.6149 | 3.3615 | 2.8486 | 3.9337 | 3.3188 | 2.8861 | 1.9398 | 2.8861 | 2.5894 |
Halonitromethanes | |||||||||||
14 | trichloronitromethane | 4.3098 | 3.7132 | 4.6383 | 4.2152 | 5.3143 | 4.9812 | 4.2007 * | 4.2819 * | 4.0809 | 3.3428 |
15 | tribromonitromethane | 2.7447 | 2.7705 | 5.3820 | 5.1283 | 6.4949 | 6.0793 | 4.8861 | 5.0640 | 4.7447 | 4.7139 |
Haloacetonitriles | |||||||||||
16 | dichloroacetonitrile | 4.5086 | 3.7184 | 3.2757 | 2.5481 | 3.7632 * | 2.5119 * | 3.0362 | 2.5123 | 2.8239 | 2.9808 |
17 | trichloroacetonitrile | 4.8861 | 4.2672 | 3.8979 | 2.6617 | 3.7447 | 2.6486 | 3.7447 | 3.8560 | 3.4815 | 3.0753 |
18 | bromochloroacetonitrile | 4.0132 | 3.8159 | 4.3188 | 4.1067 | 4.2757 | 4.2982 | 3.8539 | 3.3736 | 3.7212 | 3.3159 |
19 | dibromoacetonitrile | 4.7696 | 3.9655 | 4.7100 | 4.7981 | 4.7825 * | 5.0416 * | 4.2291 | 4.1282 | 4.1938 | 3.5113 |
Haloketones | |||||||||||
20 | 1,1-dichloropropanone | 2.7212 | 4.0555 | 3.0506 * | 2.2187 * | 3.3188 | 2.2263 | 2.4318 * | 2.2303 * | 2.3565 | 2.7129 |
21 | 1,1,1-trichloropropanone | 3.6576 * | 3.4857 * | 2.2803 | 2.3311 | 2.7364 | 2.3615 | 2.3872 | 1.0225 | 3.0000 | 2.2423 |
Haloacetic acids | |||||||||||
22 | chloroacetic acid | 6.0088 | 5.6592 | 2.1367 | 1.5737 | 1.9851 | 1.6179 | 1.6990 | 1.0652 | 1.6576 | 2.3448 |
23 | bromoacetic acid | 1.8861 | 3.2782 | 3.8697 | 2.5921 | 4.2111 | 2.8428 | 4.0655 | 3.3127 | 4.0000 | 3.1346 |
24 | iodoacetic acid | 2.6778 | 3.8068 | 4.3768 * | 3.8079 * | 4.7212 * | 4.305 * | 3.7447 | 2.4730 | 3.6576 | 3.8483 |
25 | dichloroacetic acid | 3.2147 | 4.0622 | 1.2967 | 1.6975 | 1.5229 | 1.7669 | 0.9208 | 1.2745 | 0.6198 | 1.1912 |
26 | bromochloroacetic acid | 5.1612 | 4.4508 | 2.0783 | 2.6122 | 2.3565 | 2.8669 | 1.1938 * | 1.9983 * | 1.6990 * | 1.8777 * |
27 | dibromoacetic acid | 4.1487 | 4.1865 | 2.2403 | 2.6637 | 2.4318 * | 2.9289 * | 1.6021 | 2.1776 | 1.8861 * | 2.2108 * |
28 | chloroiodoacetic acid | 1.8239 | 2.9267 | 4.4034 | 3.8242 | 4.5302 | 4.3246 | 4.0362 | 4.7239 | 4.1024 * | 4.8634 * |
29 | bromoiodoacetic acid | 3.7959 * | 3.8762 * | 4.2403 * | 3.8168 * | 4.0200 | 4.3157 | 3.7212 * | 4.8968 * | 3.8861 | 5.1786 |
30 | trichloroacetic acid | 3.2924 | 3.6489 | 1.4034 | 1.8108 | 1.4034 | 2.0112 | 1.0555 | 1.5905 | 1.0506 | 1.6881 |
31 | bromodichloroacetic acid | 1.4318 | 2.4029 | 2.7100 | 2.6367 | 2.9031 * | 2.8964 * | 1.7959 | 2.0658 | 1.6576 | 0.6340 |
32 | dibromochloroacetic acid | 3.5229 | 2.6718 | 2.7959 | 2.6882 | 2.8539 | 2.9584 | 1.4815 | 2.1417 | 1.4559 | 2.7074 |
33 | tribromoacetic acid | 4.4202 | 3.2073 | 3.3372 | 2.7322 | 3.6882 | 3.0113 | 2.1805 | 2.3490 | 2.6021 * | 2.9859 * |
Haloacetaldehyde | |||||||||||
34 | chloral hydrate | 2.1675 | 2.2067 | 2.2636 | 2.1046 | 2.1707 | 2.1359 | 1.3098 | 1.7185 | 1.6778 | 1.9750 |
Haloacetamides | |||||||||||
35 | dichloracetamide | 6.5229 | 6.9769 | 1.1135 | 1.4161 | 1.2798 | 1.5222 | 0.5850 | 1.5056 | 1.0506 | 1.6881 |
36 | bromochloroacetamide | 2.5686 * | 2.9516 * | 1.8539 * | 2.9712 * | 2.3565 | 3.3043 | 1.4559 | 2.8215 | 1.8239 * | 2.4295 * |
37 | dibromoacetamide | 3.0706 | 3.2043 | 4.2218 * | 3.6626 * | 4.2596 | 4.0477 | 3.9586 | 3.6467 | 3.6198 | 2.7807 |
38 | chloroiodoacetamide | 2.6576 | 3.3142 | 3.7212 | 3.5437 | 4.1192 | 4.0810 | 2.7212 | 2.0333 | 2.5376 | 2.1670 |
39 | bromoiodoacetamide | 3.3768 | 4.4729 | 3.1163 | 4.1762 | 3.7959 * | 4.7536 * | 2.2291 | 1.9651 | 2.0706 | 2.4718 |
40 | diiodoacetamide | 1.4318 | 1.1768 | 2.7825 | 3.5724 | 3.0482 | 4.1155 | 2.2218 | 2.1941 | 2.1938 | 2.1785 |
41 | trichloroacetamide | 2.0000 | 1.8559 | 0.3565 | 1.5288 | 0.7825 * | 1.6577 * | 1.0706 | 1.4651 | 1.5850 | 2.1329 |
42 | bromodichloroacetamide | 4.3098 * | 4.099 * | 3.6198 | 2.9951 | 3.8239 | 3.3331 | 4.0315 | 2.6693 | 3.7959 | 2.7569 |
43 | dibromochloroacetamide | 4.3768 * | 4.2953 * | 3.9566 | 3.6865 | 4.3188 | 4.0764 | 3.9586 | 3.8000 | 3.6383 | 3.1107 |
44 | tribromoacetamide | 2.1308 | 1.5148 | 4.3233 | 4.3703 | 4.6676 | 4.8106 | 4.4437 | 4.7359 | 4.2147 * | 3.4421 * |
Nitrosamines | |||||||||||
45 | n-nitrosodimethylamine | 2.9208 | 3.0246 | - | - | - | - | - | - | - | - |
46 | n-nitrosodiethylamine | 7.4202 | 7.1686 | - | - | - | - | - | - | - | - |
47 | n-nitrosopiperidine | 3.8861 | 4.6292 | - | - | - | - | - | - | - | - |
48 | n-nitrosomorpholine | 3.8539 | 3.3096 | - | - | - | - | - | - | - | - |
49 | nitrosodi-n-butylamine | 3.5850 * | 3.4285 * | - | - | - | - | - | - | - | - |
Furanone | |||||||||||
50 | 3-chloro-4-(dichloromethyl)-5- | 4.7447 | 3.1323 | 5.2596 | 6.0139 | 5.6108 | 6.4454 | 4.8861 | 4.3949 | 4.9586 | 4.7578 |
Endpoint | Equation a | Modeling b | Internal Validation c | External Validation d | Golbraikh & Tropsha e |
---|---|---|---|---|---|
X-Microtox | pEC50 = −11.8502 + 0.1230 SpDiam_B(m) + 4.9744 AVS_B(v) + 0.8805 Eig05_AEA(dm) − 3.3986 SddsN | ntr = 40, R2 = 0.7152, = 0.6826, RMSEtr = 0.7682, F = 21.9717 | = 0.6374, RMSEcv = 0.8668, = 0.6216, = 0.1034, = −0.2452 | ntest = 10, RMSEext = 0.2040, = 0.8660, = 0.8508, = 0.8496, = 0.9799, CCC = 0.9115 = 0.7185, = 0.1439 | k = 1.0136, k’ = 0.9837, = 0.8018, = 0.8584 |
GSH+ | pECIR1.5 = −2.4744 + 0.1022C% + 0.3184SpDiam_B(m) + 0.0725 P_VSA_LogP_8+ 0.2132 T(N..Br) | ntr = 36, R2 = 0.7837, = 0.7558, RMSEtr = 0.5927, F = 28.0843 | = 0.6956, RMSEcv = 0.7032, = 0.6644, = 0.1121, = −0.2323 | ntest = 9, RMSEext = 0.6010, = 0.7715, = 0.7502, = 0.7502, = 0.7776, CCC = 0.8500, = 0.6558, = 0.1915 | k = 1.0596, k’ = 0.9119, = 0.6964, = 0.7709 |
GSH- | pECIR1.5 = −2.4133 + 0.0894 C% + 0.3829SpDiam_B(m) + 0.0835 P_VSA_LogP_8 + 0.2270 T(N..Br) | ntr = 36, R2 = 0.8166, = 0.7929, RMSEtr = 0.5936, F = 34.5096 | = 0.7332, RMSEcv = 0.7160, = 0.6634, = 0.1140, = −0.2349 | ntest = 9, RMSEext = 0.6578, = 0.7593, = 0.7436, = 0.7430, = 0.7748, CCC = 0.8703, = 0.6688, = 0.0426 | k = 0.9659, k’ = 0.9969, = 0.7376, = 0.7510 |
DNA+ | pECIR1.5 = 1.8732 + 0.0493 P_VSA_LogP_7 − 0.2258 Mor04s + 0.2798 T(N..Br) − 0.8971 T(N..I) | ntr = 36, R2 = 0.7019, = 0.6635, RMSEtr = 0.7113, F = 18.2520 | = 0.6287, RMSEcv = 0.7940, = 0.6338, = 0.1139, = −0.2471 | ntest = 9, RMSEext = 0.5570, = 0.8232, = 0.7482, = 0.7228, = 0.8173, CCC = 0.8781, = 0.7541, = 0.0264 | k = 0.8805, k ’= 1.0974, = 0.8132, = 0.8186 |
DNA- | pECIR1.5 = 0.9105 + 0.3091Sv + 0.0493 P_VSA_LogP_7 + 0.2008 Mor03s − 1.0911 T(N..I) | ntr = 36, R2 = 0.7164, = 0.6786, RMSEtr = 0.6540, F = 18.9496 | = 0.6221, RMSEcv = 0.7550, = 0.5291, = 0.1200, = −0.2504 | ntest = 9, RMSEext = 0.4991, = 0.7774, = 0.7505, = 0.7500, = 0.8348, CCC = 0.8787, = 0.6920, = 0.0076 | k = 0.9538, k’ = 1.0145, = 0.7643, = 0.7664 |
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Qin, L.; Zhang, X.; Chen, Y.; Mo, L.; Zeng, H.; Liang, Y. Predictive QSAR Models for the Toxicity of Disinfection Byproducts. Molecules 2017, 22, 1671. https://doi.org/10.3390/molecules22101671
Qin L, Zhang X, Chen Y, Mo L, Zeng H, Liang Y. Predictive QSAR Models for the Toxicity of Disinfection Byproducts. Molecules. 2017; 22(10):1671. https://doi.org/10.3390/molecules22101671
Chicago/Turabian StyleQin, Litang, Xin Zhang, Yuhan Chen, Lingyun Mo, Honghu Zeng, and Yanpeng Liang. 2017. "Predictive QSAR Models for the Toxicity of Disinfection Byproducts" Molecules 22, no. 10: 1671. https://doi.org/10.3390/molecules22101671