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Acta Phys. -Chim. Sin.  2015, Vol. 31 Issue (12): 2395-2404    DOI: 10.3866/PKU.WHXB201510142
BIOPHYSICAL CHEMISTRY     
Molecular Docking and Receptor-Based 3D-QSAR Studies on Aromatic Thiazine Derivatives as Selective Aldose Reductase Inhibitors
Shu-Zhen. ZHANG,Chao. ZHENG,Chang-Jin. ZHU*()
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Abstract  

Aromatic thiazine derivatives were proved to be potent aldose reductase inhibitors (ARIs) with high selectivity for aldose reductase (ALr2) over aldehyde reductase (ALR1). Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies are conducted on a dataset of 44 molecules to explore the interactions between aromatic thiazine derivatives and ALr2. The superposition of ALr2 and ALR1 active sites indicate that residues Leu 300 and Cys 298 from ALr2 may explain the good selectivity of the most active compound 1m. The comparative molecular field analysis (CoMFA) model (q2 = 0.649, r2 = 0.934; q2: cross-validated correlation coefficient, r2: non-cross-validated correlation coefficient) and comparative molecular similarity indices analysis (CoMSIA) model (q2 = 0.746, r2 = 0.971), based on the docking conformations of these compounds, are obtained to identify the key structures impacting their inhibitory potencies. The predictive power of the developed models is further validated by a test set of seven compounds, resulting in predictive rPred2 values of 0.748 for CoMFA and 0.828 for CoMSIA. 3D contour maps, drawn from 3D-QSAR models, reveal that future modifications of substituents at the C3 and C4 positions of the benzyl ring and the C5 and C7 positions of the benzothiazine-1, 1-dioxide core might be favorable for improving the biological activity, which are in good accordance with the C7 modification results reported in our earlier work. The information rendered by 3DQSAR models could be helpful in the rational design of novel ARIs with good inhibitory activity to treat diabetic complications in the future.



Key wordsAldose reductase inhibitor      Molecular docking      3D-QSAR      Selectivity      Aromatic thiazine derivative     
Received: 10 August 2015      Published: 14 October 2015
MSC2000:  O641  
Fund:  the National Natural Science Foundation of China(21272025);Science and Technology Commission of Beijing,China(Z131100004013003)
Corresponding Authors: Chang-Jin. ZHU     E-mail: zcj@bit.edu.cn
Cite this article:

Shu-Zhen. ZHANG,Chao. ZHENG,Chang-Jin. ZHU. Molecular Docking and Receptor-Based 3D-QSAR Studies on Aromatic Thiazine Derivatives as Selective Aldose Reductase Inhibitors. Acta Phys. -Chim. Sin., 2015, 31(12): 2395-2404.

URL:

http://www.whxb.pku.edu.cn/10.3866/PKU.WHXB201510142     OR     http://www.whxb.pku.edu.cn/Y2015/V31/I12/2395

Compound R1 R2 ALR2 pIC50 ALR1 IC50/(μ mol∙L–1) MolDock Score
1a H 2-F, 4-Br 6.903 70.3 –119.1
1b H 3-NO2 6.660 55.8 –117.6
 1c* H 4-CF3 6.011 42%a –109.4
1d H 2, 4, 5-F3 6.955 –120.9
1e H H 3.994 –92.9
1f F 2-F, 4-Br 7.046 121.9 –122.2
1g F 3-NO2 6.967 61.9 –120.1
1h F 4-CF3 6.031 40%a –112.6
 1i* F 2, 4, 5-F3 7.180 80.9 –124.5
1j Cl 2-F, 4-Br 7.387 58.9 –125.8
1k Cl 3-NO2 7.027 82.5 –124.8
1l Cl 4-CF3 6.225 45%a –114.9
 1m Cl 2, 4, 5-F3 7.495 50.6 –126.4
1n Br 2-F, 4-Br 7.149 69.4 –125.5
 1o* Br 3-NO2 6.936 102.9 –120.8
1p Br 4-CF3 6.171 109.6 –110.2
1q Br 2, 4, 5-F3 7.284 54.1 –125.6
2a Cl 2-F, 4-Br 7.357 36.6%b –125.2
 2b* Cl 3-NO2 7.032 40.2%b –122.0
2c Cl 4-CF3 5.996 42.3%b –108.7
2d Cl 2, 4, 5-F3 7.420 36.5%b –126.3
2e Cl 4-OCH3 5.184 32.3%b –103.6
2f Br 2-F, 4-Br 7.161 44.9%b –118.4
2g Br 3-NO2 7.009 31.5%b –116.5
2h Br 4-CF3 6.015 43.3%b –109.5
2i Br 2, 4, 5-F3 7.180 44.2%b –116.8
2j Br 4-OCH3 4.947 27.9%b –98.7
2k CH3 2-F, 4-Br 6.896 24.6%b –115.2
2l CH3 3-NO2 6.844 23.2%b –114.0
 2m CH3 4-CF3 6.000 20.5%b –108.7
2n CH3 2, 4, 5-F3 7.076 35.4%b –119.0
2o CH3 4-OCH3 5.203 17.7%b –104.8
3a H 2, 4, 5-F3 6.229 18%c –107.2
 3b* H 4-CF3 5.213 –105.8
3c H 2-F, 4-Br 6.959 11%c –118.6
3d H 3-NO2 6.854 26%c –116.3
3e H 2-F 5.672 –106.8
 4a* H 2, 4, 5-F3 6.469 28%c –112.6
4b H 3, 5-(CF3)2 4.982 –101.7
4c H 4-CF3 5.276 –105.9
4d H 2-F 5.762 –109.7
 5a* H 2-F, 4-Br 4.234 –95.2
5b H 3-NO2 4.128 –94.6
5c H 2, 4, 5-F3 4.854 –98.9
*test set compounds. a, b, c Inhibitory effect against ALR1 estimated at 100, 50, and 10 μmol∙L–1, respectively.
 
 
 
 
PLS parameter CoMFA CoMSIA
q2 0.649 0.746
ONC 5 8
r2 0.934 0.971
SD 0.112 0.114
F 94.533 111.499
$r^2_{\rm Pred}$ 0.748 0.828
relative field contribution
steric/% 74.4 12.3
electrostatic/% 25.6 24.2
hydrophobic/% 41.9
acceptor/%   21.6
q2: cross-validated correlation coefficient; ONC: optimum number of component; r2: non-cross-validated correlation coefficient; SD: standard deviation; F: statistical squared deviation ratio; $r^2_{\rm Pred}$ : predicted correlation coefficient
 
No. Actual pIC50 CoMFA CoMSIA
Predicted pIC50 Residual Predicted pIC50 Residual
1a 6.903 7.007 –0.104 6.955 –0.052
1b 6.660 6.798 –0.138 6.776 –0.116
1c* 6.011 6.144 –0.133 6.098 –0.087
1d 6.955 6.962 –0.007 7.073 –0.118
1e 3.994 4.766 0.772 4.653 0.659
1f 7.046 7.049 –0.003 7.038 0.008
1g 6.967 6.874 0.093 6.875 0.092
1h 6.031 6.071 –0.040 6.102 –0.071
1i* 7.180 6.993 0.187 6.884 0.296
1j 7.387 7.273 0.114 7.161 0.226
1k 7.027 7.103 –0.076 7.006 0.021
1l 6.225 6.191 0.036 6.205 0.020
1m 7.495 7.180 0.315 7.295 0.200
1n 7.149 7.238 –0.091 7.225 –0.076
1o* 6.936 7.082 –0.146 7.028 –0.092
1p 6.171 6.196 –0.025 6.265 –0.094
1q 7.284 7.383 –0.099 7.371 –0.087
2a 7.367 7.056 0.301 7.260 0.097
2b* 7.032 6.882 0.150 7.117 –0.085
2c 5.996 6.098 –0.102 6.114 –0.118
2d 7.420 7.319 0.101 7.163 0.257
2e 5.184 4.973 0.211 5.243 –0.059
2f 7.161 7.098 0.063 7.256 –0.095
2g 7.009 6.853 0.156 7.113 –0.104
2h 6.015 6.177 –0.162 6.007 0.008
2i 7.180 7.021 0.159 7.214 –0.034
2j 4.947 5.184 –0.237 4.921 0.026
2k 6.896 7.124 –0.228 7.150 –0.253
2l 6.845 6.668 0.177 6.731 0.114
2m 6.000 6.172 –0.172 5.917 0.083
2n 7.076 7.201 –0.125 7.088 0.102
2o 5.203 4.961 0.242 5.114 0.059
3a 6.229 6.323 –0.094 6.423 –0.234
3b* 5.213 5.377 –0.164 5.392 –0.179
3c 6.959 6.675 0.284 6.854 0.105
3d 6.854 6.759 0.095 6.653 0.201
3e 5.672 5.881 –0.209 5.866 –0.194
4a* 6.469 6.254 0.215 6.286 0.183
4b 4.982 4.921 0.061 4.862 0.120
4c 5.276 5.256 0.020 5.165 0.111
4d 5.762 6.025 –0.263 5.817 –0.055
5a* 4.234 4.596 –0.362 4.435 –0.201
5b 4.128 4.283 –0.155 4.317 –0.189
5c 4.854 4.653 0.201 4.641 0.213
*test set compounds
 
 
 
 
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