A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Selection of Training and Test Sets
2.2. Results of CoMFA and CoMSIA
2.3. Contour Maps
2.4. Molecular Docking
2.5. MD Simulations
3. Materials and Experimental Methods
3.1. Dataset
3.2. Molecular Modeling and Alignment
3.3. Docking Simulation
3.4. CoMFA and CoMSIA Calculations
3.5. Statistical Validation
3.6. Molecular Dynamics Simulations
4. Conclusions
Acknowledgement
References
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PLS analysis | Alignment methods | |||||
---|---|---|---|---|---|---|
I | II | III | ||||
CoMFA | CoMSIA | CoMFA | CoMSIA | CoMFA | CoMSIA | |
q2 | 0.536 | 0.556 | −0.035 | 0.263 | 0.311 | 0.400 |
SEP | 0.642 | 0.595 | 0.909 | 0.759 | 0.741 | 0.699 |
PCs | 8 | 3 | 3 | 2 | 3 | 4 |
r2ncv | 0.974 | 0.779 | 0.873 | 0.810 | 0.897 | 0.843 |
SEE | 0.151 | 0.420 | 0.318 | 0.385 | 0.287 | 0.357 |
F value | 207.641 | 57.509 | 112.475 | 106.868 | 141.747 | 64.605 |
r2cv(mean) | 0.630 | 0.606 | 0.169 | 0.273 | 0.401 | 0.390 |
r2bs | 0.989 | 0.820 | - | - | - | - |
SEEbs | 0.099 | 0.374 | - | - | - | - |
r2pred | 0.810 | 0.669 | 0.416 | 0.480 | 0.444 | 0.156 |
Relative Contribution (%) | ||||||
S | 0.496 | 0.250 | 0.348 | - | 0.475 | 1.000 |
E | 0.504 | 0.503 | 0.652 | 0.483 | 0.525 | - |
H | - | - | - | 0.517 | - | - |
D | - | 0.247 | - | - | - | - |
A | - | - | - | - | - |
Model | r2pred | r2test | (r2test − r2o)/r2test | k | r2m |
---|---|---|---|---|---|
CoMFA | 0.810 | 0.807 | 0.013 | 0.993 | 0.723 |
CoMSIA | 0.669 | 0.677 | 0.054 | 0.998 | 0.548 |
Compd. | R | Experimental pIC50 | Predicted pIC50 | ||
---|---|---|---|---|---|
CoMFA | CoMSIA | ||||
1 | Ph | 5.699 | 5.344 | 5.391 | |
2* | Et | 4.699 | 5.063 | 4.954 | |
3 | i-Pr | 4.886 | 5.013 | 4.978 | |
4 | t-Bu | 5.602 | 5.569 | 4.973 | |
5 | c-Pr | 4.921 | 4.773 | 5.374 | |
6* | c-Pentyl | 4.276 | 4.735 | 5.375 | |
7 | c-Heptanyl | 4.456 | 4.380 | 5.364 | |
8* | Bn | 4.444 | 4.401 | 4.736 | |
9 | MeOCH2CH2 | 4.658 | 4.507 | 4.405 | |
10 | Benzoyl | 4.041 | 4.213 | 4.249 | |
11 | 1-Naphthyl | 5.495 | 5.595 | 4.816 | |
Compd. | R1 | R2 | Exprimental pIC50 | Predicted pIC50 | |
CoMFA | CoMSIA | ||||
12 | H | H | 4.495 | 4.687 | 5.440 |
13 | Me | H | 5.398 | 5.261 | 5.001 |
14 * | Et | H | 5.824 | 5.799 | 5.203 |
15 | n-Pr | H | 5.638 | 5.614 | 5.837 |
16 * | c-Pr | H | 6.328 | 6.051 | 5.811 |
Compd. | R | Experimental pIC50 | Predicted pIC50 | ||
CoMFA | CoMSIA | ||||
17 | 4-Me | 5.569 | 5.714 | 5.436 | |
18 * | 4-Cl | 5.432 | 5.348 | 5.263 | |
19 | 4-MeO | 5.721 | 5.444 | 4.948 | |
20 | 4-i-Pr | 5.585 | 5.516 | 5.337 | |
21 | 4-t-Bu | 4.863 | 4.968 | 4.868 | |
22 | 4-Br | 5.509 | 5.357 | 5.261 | |
23 | 4-NO2 | 5.004 | 5.168 | 5.527 | |
24 * | 4-CN | 5.161 | 4.859 | 5.153 | |
25 | 4-BnO | 5.569 | 5.582 | 5.290 | |
26 * | 4-Ac | 5.161 | 4.910 | 5.010 | |
27 | 4-EtOC(=O)- | 4.971 | 4.949 | 4.958 | |
28 | 4-NMe2 | 5.155 | 5.405 | 5.060 | |
29 | 4-(Morphorin-1-yl) | 4.762 | 4.809 | 4.889 | |
30 | 4-AcNH- | 5.284 | 5.515 | 5.908 | |
31 | 4-NH2 | 5.699 | 5.795 | 5.811 | |
32 | 4-BnOC(=O)NH- | 6.337 | 6.322 | 6.218 | |
33 | 2-Me | 5.444 | 5.488 | 5.342 | |
34 | 2-Cl | 5.959 | 5.778 | 5.473 | |
35 | 2-MeO | 5.585 | 5.599 | 5.619 | |
36 | 2-F | 5.699 | 5.720 | 5.524 | |
Compd. | R | Experimental pIC50 | Predicted pIC50 | ||
CoMFA | CoMSIA | ||||
37 | 2-MeS | 5.602 | 5.711 | 5.511 | |
38 * | 3-Me | 5.032 | 5.160 | 5.348 | |
39 | 3-Cl | 4.947 | 5.088 | 5.375 | |
40 * | 3-MeO | 4.839 | 5.507 | 5.107 | |
41 | 2,4-Di-MeO | 5.602 | 5.457 | 5.365 | |
42 * | 2,4-Di-Cl | 5.367 | 5.787 | 5.345 | |
43 | 3,5-Di-Cl | 4.569 | 4.564 | 5.374 | |
Compd. | R1 | R2 | Experimental pIC50 | Predicted pIC50 | |
CoMFA | CoMSIA | ||||
44 | MeOC(=O)NH- | Cl | 6.027 | 5.884 | 5.920 |
45 | EtOC(=O)NH- | Cl | 6.509 | 6.147 | 5.997 |
46 | n-BuOC(=O)NH- | Cl | 6.638 | 6.765 | 6.124 |
47 | i-BuOC(=O)NH- | Cl | 6.824 | 6.841 | 6.114 |
48 * | t-BuOC(=O)NH- | Cl | 6.721 | 6.299 | 6.025 |
49 | i-BuOC(=O)N(Ph)- | Cl | 5.824 | 5.772 | 5.824 |
50 * | MeNHC(=O)NH- | Cl | 5.770 | 5.765 | 6.309 |
51 | t-BuNHC(=O)NH- | Cl | 6.155 | 6.234 | 6.451 |
52 | t-BuOC(=O)NH- | Me | 6.678 | 6.530 | 6.624 |
53 | PhOC(=O)NH- | Me | 6.137 | 6.221 | 6.165 |
54 | EtOC(=O)N(Me)- | Me | 5.000 | 5.067 | 5.592 |
55 | t-BuOC(=O)O- | Me | 5.538 | 5.684 | 5.918 |
56 | EtC(=O)NH- | Me | 4.876 | 4.854 | 5.679 |
57 | n-PrC(=O)NH- | Me | 5.638 | 5.541 | 5.719 |
58 * | n-BuC(=O)NH- | Me | 5.824 | 5.612 | 5.715 |
59 | BnC(=O)NH- | Me | 5.420 | 5.518 | 5.487 |
60 * | PhC(=O)NH- | Me | 6.237 | 5.748 | 5.971 |
Compd. | R1-R2 | Experimental pIC50 | Predicted pIC50 | ||
CoMFA | CoMSIA | ||||
61 | 3-NHC(=O)NH-4 | 4.824 | 4.639 | 4.696 | |
62 | 3-CH2C(=O)NH-4 | 4.569 | 4.696 | 4.842 | |
63 * | 3-SC(=O)NH-4 | 4.824 | 5.106 | 4.972 | |
64 * | 3-NHC(=O)O-4 | 4.854 | 5.437 | 5.382 | |
Compd. | R1 | R2 | Experimental pIC50 | Predicted pIC50 | |
CoMFA | CoMSIA | ||||
65 | Et | 6.854 | 6.827 | 6.824 | |
66 | n-Pr | 7.347 | 7.409 | 7.020 | |
67* | c-Pr | 6.987 | 6.996 | 6.470 | |
68 | n-Pr | 7.699 | 7.577 | 7.681 | |
69 | n-Bu | 7.523 | 7.539 | 7.795 | |
70 | c-Pr | 7.824 | 7.960 | 7.422 | |
71 | c-Pr | 7.081 | 7.100 | 6.889 |
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Share and Cite
Hao, M.; Ren, H.; Luo, F.; Zhang, S.; Qiu, J.; Ji, M.; Si, H.; Li, G. A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors. Int. J. Mol. Sci. 2012, 13, 7057-7079. https://doi.org/10.3390/ijms13067057
Hao M, Ren H, Luo F, Zhang S, Qiu J, Ji M, Si H, Li G. A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors. International Journal of Molecular Sciences. 2012; 13(6):7057-7079. https://doi.org/10.3390/ijms13067057
Chicago/Turabian StyleHao, Ming, Hong Ren, Fang Luo, Shuwei Zhang, Jieshan Qiu, Mingjuan Ji, Hongzong Si, and Guohui Li. 2012. "A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors" International Journal of Molecular Sciences 13, no. 6: 7057-7079. https://doi.org/10.3390/ijms13067057