Non-Linear Quantitative Structure–Activity Relationships Modelling, Mechanistic Study and In-Silico Design of Flavonoids as Potent Antioxidants
Abstract
:1. Introduction
2. Results and Discussion
2.1. Linear PLS-QSAR Model
2.2. Interpretation of the PLS-QSAR Model
2.3. Non-Linear ANN-QSAR Model
2.4. Validation of the ANN-QSAR Model
2.5. Interpretation of the ANN-QSAR Model
2.6. Mechanism of Hydrogen Abstraction Transfer by Peroxyl Radical
2.7. In-Silico Design of Potent Flavonoid-Based Antioxidants
3. Materials and Methods
3.1. Chemicals and Instruments
3.2. Preparation of Standards and Solutions
3.3. Automatic ORAC Assay
3.4. QSAR model Development
3.4.1. Molecular Descriptors
3.4.2. Conformational Analysis and Geometry Optimization
3.4.3. Selection of Molecular Descriptors for QSAR Modelling
3.5. QSAR Model Development
3.6. QSAR Model Validation
3.7. In-Silico Design of Potent Flavonoid-Based Antioxidants
3.8. Theoretical Methods
3.8.1. Partial Least Squares (PLS)
3.8.2. Artificial Neural Networks (ANNs)
Partial Derivative (PaD) Method
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Genistein | Quercetin | |||
---|---|---|---|---|
Gas Phase | Water | Gas Phase | Water | |
Overall reaction | ||||
ROH + PO•→RO• + POH | 5.6 | 0.8 | −3.1 | −5.6 |
HAT mechanism | ||||
ROH→RO• + H• | 83.8 | 85.3 | 75.1 | 78.9 |
PO• + H•→POH | −78.2 | −84.5 | −78.2 | −84.5 |
SPLET mechanism | ||||
ROH + PO•→RO− + POH•+ | 134.2 | 32.9 | 126.8 | 31.9 |
RO− + POH•+→RO• + POH | −128.6 | −32.1 | −129.8 | −37.5 |
SETPL mechanism | ||||
ROH + PO•→ROH•+ + PO− | 144.6 | 32.6 | 137.6 | 28.0 |
ROH•+ + PO−→RO• + POH | −138.9 | −31.7 | −140.7 | −33.6 |
R1 | R2 | R3 | R4 | R5 | R6 | R7 | R8 | R1′ | R2′ | R3′ | R4′ | R5′ | R6′ |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Top 55 compounds (ORAC > 5) | |||||||||||||
0 | 0 | 11 | 1 | 7 | 20 | 19 | 17 | 0 | 20 | 20 | 18 | 16 | 7 |
Bottom 18 compounds (ORAC < 2) | |||||||||||||
0 | 0 | 0 | 5 | 0 | 9 | 5 | 0 | 2 | 0 | 5 | 2 | 3 | 2 |
# | Name | Molecular Structure | ln (ORAC) | PLS | ANN |
---|---|---|---|---|---|
1 | Genistein | 2.267 ± 0.008 | 0.953 | 2.165 ± 0.101 | |
2 | Naringenin | 2.141 ± 0.014 | 0.939 | 2.152 ± 0.072 | |
3 | Scutellarin | 2.042 ± 0.014 | 1.567 | 2.171 ± 0.216 | |
4 | 3,5,7,8,3′,4′-Hexahydroxyflavone | 2.026 ± 0.001 | 1.944 | 2.038 ± 0.216 | |
5 | Epicatechin | 2.018 ± 0.004 | 1.579 | 1.326 ± 0.222 | |
6 | Kaempferol | 2.018 ± 0.018 | 1.331 | 1.836 ± 0.085 | |
7 | Eriodictyol | 2.013 ± 0.006 | 1.473 | 1.962 ± 0.098 | |
8 | Apigenin | 2.010 ± 0.000 | 0.796 | 1.968 ± 0.097 | |
9 | Quercetin | 1.970 ± 0.003 | 1.525 | 1.979 ± 0.059 | |
10 | Liquiritigenin | 1.970 ± 0.003 | 0.948 | 2.062 ± 0.081 | |
11 | Fisetin | 1.959 ± 0.022 | 1.368 | 1.798 ± 0.060 | |
12 | Taxifolin | 1.942 ± 0.004 | 1.570 | 1.922 ± 0.081 | |
13 | Hesperetin | 1.938 ± 0.014 | 1.239 | 2.035 ± 0.062 | |
14 | 3,3′,4′-Trihydroxyflavone | 1.869 ± 0.019 | 1.143 | 1.873 ± 0.033 | |
15 | 7,3′,4′-Trihydroxyflavone | 1.691 ± 0.016 | 1.368 | 1.658 ± 0.068 | |
16 | Diosmetin | 1.656 ± 0.001 | 1.069 | 1.728 ± 0.066 | |
17 | Luteolin | 1.611 ± 0.013 | 1.322 | 1.730 ± 0.065 | |
18 | Morin | 1.517 ± 0.006 | 1.424 | 1.588 ± 0.095 | |
19 | Epigallocatechin | 1.225 ± 0.020 | 1.932 | 1.227 ± 0.101 | |
20 | 5,3′,4′-Trihydroxyflavone | 1.223 ± 0.038 | 1.141 | 1.206 ± 0.041 | |
21 | Ampelopsin | 1.204 ± 0.038 | 1.842 | 1.245 ± 0.080 | |
22 | Myricetin | 1.173 ± 0.000 | 1.721 | 1.248 ± 0.077 | |
23 | Wogonin | 1.077 ± 0.000 | 0.697 | 0.924 ± 0.137 | |
24 | 7,8-Dihydroxyflavone | 1.051 ± 0.002 | 1.322 | 1.097 ± 0.112 | |
25 | Chrysin | 1.016 ± 0.001 | 0.226 | 1.051 ± 0.068 | |
26 | Pinocembrin | 1.013 ± 0.011 | 0.225 | 0.978 ± 0.105 | |
27 | Catechin | 1.012 ± 0.018 | 1.597 | 1.266 ± 0.243 | |
28 | Eupatilin | 0.891 ± 0.013 | 0.556 | 0.799 ± 0.119 | |
29 | Baicalein | 0.816 ± 0.003 | 1.382 | 0.730 ± 0.139 | |
30 | Pectolinarigenin | 0.788 ± 0.023 | 0.515 | 0.832 ± 0.084 | |
31 | 3,5-Dihydroxyflavone | 0.767 ± 0.046 | 0.846 | 0.761 ± 0.095 | |
32 | Alpinetin | 0.492 ± 0.009 | 0.410 | 0.505 ± 0.095 | |
33 | Galangin | 0.328 ± 0.030 | 1.063 | 0.539 ± 0.123 | |
34 | Genkwanin | −0.072 ± 0.058 | 0.667 | −0.031 ± 0.131 | |
35 | Primuletin | −0.969 ± 0.004 | 0.044 | −1.055 ± 0.164 | |
36 | Tectochrysin | −1.581 ± 0.079 | −1.306 | −1.575 ± 0.247 |
# | Compound Name | n (OH) | ETE (1) | PA (1) | BDEmin (1) | HE |
---|---|---|---|---|---|---|
1 | Genistein | 3 | 89.175 | 33.630 | 83.987 | −17.606 |
2 | Naringenin | 3 | 90.557 | 33.240 | 84.979 | −19.251 |
3 | Scutellarin | 4 | 78.864 | 35.648 | 75.694 | −17.513 |
4 | 3,5,7,8,3′,4′-Hexahydroxyflavone | 6 | 67.389 | 42.831 | 71.402 | −20.148 |
5 | Epicatechin | 5 | 68.664 | 49.233 | 79.080 | −27.271 |
6 | Kaempferol | 4 | 84.259 | 33.472 | 78.913 | −17.382 |
7 | Eriodictyol | 4 | 84.665 | 33.190 | 79.037 | −21.559 |
8 | Apigenin | 3 | 89.514 | 35.499 | 86.196 | −18.219 |
9 | Quercetin | 5 | 83.812 | 32.554 | 77.549 | −19.749 |
10 | Liquiritigenin | 2 | 89.619 | 33.975 | 84.776 | −19.203 |
11 | Fisetin | 4 | 84.471 | 33.907 | 79.560 | −19.860 |
12 | Taxifolin | 5 | 85.166 | 32.360 | 78.708 | −23.422 |
13 | Hesperetin | 3 | 85.930 | 33.240 | 80.352 | −17.828 |
14 | 3,3′,4′-Trihydroxyflavone | 3 | 73.742 | 43.939 | 78.863 | −13.813 |
15 | 7,3′,4′-Trihydroxyflavone | 3 | 84.339 | 34.749 | 80.271 | −21.503 |
16 | Diosmetin | 3 | 87.176 | 33.782 | 82.141 | −16.976 |
17 | Luteolin | 4 | 84.601 | 34.584 | 80.367 | −20.391 |
18 | Morin | 5 | 70.199 | 47.284 | 78.665 | −21.759 |
19 | Epigallocatechin | 6 | 78.699 | 35.785 | 75.666 | −27.626 |
20 | 5,3′,4′-Trihydroxyflavone | 3 | 84.893 | 34.572 | 80.647 | −15.957 |
21 | Ampelopsin | 6 | 82.652 | 32.448 | 76.283 | −25.878 |
22 | Myricetin | 6 | 81.442 | 33.218 | 75.843 | −21.695 |
23 | Wogonin | 2 | 89.929 | 33.535 | 84.646 | −11.865 |
24 | 7,8-Dihydroxyflavone | 2 | 84.537 | 32.175 | 77.894 | −14.759 |
25 | Chrysin | 2 | 96.442 | 33.750 | 91.375 | −13.037 |
26 | Pinocembrin | 2 | 97.500 | 33.197 | 91.879 | −13.970 |
27 | Catechin | 5 | 68.136 | 49.725 | 79.043 | −27.785 |
28 | Eupatilin | 2 | 92.534 | 33.579 | 87.295 | −13.554 |
29 | Baicalein | 3 | 81.439 | 33.164 | 75.786 | −12.133 |
30 | Pectolinarigenin | 2 | 92.425 | 33.712 | 87.319 | −12.482 |
31 | 3,5-Dihydroxyflavone | 2 | 83.211 | 36.125 | 80.518 | −7.727 |
32 | Alpinetin | 1 | 95.985 | 33.690 | 90.857 | −17.037 |
33 | Galangin | 3 | 85.569 | 33.430 | 80.181 | −12.605 |
34 | Genkwanin | 2 | 89.997 | 35.002 | 86.181 | −14.537 |
35 | Primuletin | 1 | 89.804 | 40.053 | 91.039 | −8.315 |
36 | Tectochrysin | 1 | 108.611 | 39.485 | 109.278 | −9.220 |
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Žuvela, P.; David, J.; Yang, X.; Huang, D.; Wong, M.W. Non-Linear Quantitative Structure–Activity Relationships Modelling, Mechanistic Study and In-Silico Design of Flavonoids as Potent Antioxidants. Int. J. Mol. Sci. 2019, 20, 2328. https://doi.org/10.3390/ijms20092328
Žuvela P, David J, Yang X, Huang D, Wong MW. Non-Linear Quantitative Structure–Activity Relationships Modelling, Mechanistic Study and In-Silico Design of Flavonoids as Potent Antioxidants. International Journal of Molecular Sciences. 2019; 20(9):2328. https://doi.org/10.3390/ijms20092328
Chicago/Turabian StyleŽuvela, Petar, Jonathan David, Xin Yang, Dejian Huang, and Ming Wah Wong. 2019. "Non-Linear Quantitative Structure–Activity Relationships Modelling, Mechanistic Study and In-Silico Design of Flavonoids as Potent Antioxidants" International Journal of Molecular Sciences 20, no. 9: 2328. https://doi.org/10.3390/ijms20092328