3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Sets
2.2. Molecular Modeling and Alignment
2.3. SOMFA 3D-QSAR Models
3. Results and Discussion
4. Conclusions
Acknowledgments
References
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Compd No. | R1 | R2 | R3 | Compd No. | R1 | R2 | R3 |
---|---|---|---|---|---|---|---|
1 | H | H | H | 29 | Cl | CH3 | H |
2 | CH3 | H | H | 30* | Cl | H | CH3 |
3 | CF3 | H | H | 31 | CH3 | Cl | H |
4 | H | CF3 | H | 32 | Br | CH3 | H |
5* | Cl | H | H | 33 | CN | CH3 | H |
6 | H | Cl | H | 34 | CF3S | CH3 | H |
7 | H | H | Cl | 35* | CF3O | CH3 | H |
8 | Br | H | H | ||||
9 | CN | H | H | 36 | | H | H |
10* | -CH2CN | H | H | ||||
11 | CF3S | H | H | ||||
12 | CF3SO | H | H | 37 | | H | H |
13 | CF3SO2 | H | H | ||||
14 | CH3S | H | H | ||||
15* | CH3SO | H | H | 38 | | H | H |
16 | CH3SO2 | H | H | ||||
17 | CF3O | H | H | ||||
18 | CH3O | H | H | 39 | | H | H |
19 | OH | H | H | ||||
20* | NO2 | H | H | ||||
21 | H2N | H | H | 40* | | H | H |
22 | CH3CO | H | H | ||||
23 | H2NCO | H | H | ||||
24 | HOOC- | H | H | 41 | | H | H |
25* | CH3O2C- | H | H | ||||
26 | CF3 | CH3 | H | ||||
27 | CF3 | C2H5 | H | 42 | | H | H |
28 | C2F5 | CH3 | H |
| |||
---|---|---|---|
Compd No. | R | Compd No. | R |
43 | -CH3 | 48 | |
3 | | 49 | |
44 | | 50* | |
45* | | 51 | |
46 | | 52 | |
47 | | 53* | |
Alignment No. | 1st atom | 2nd atom | 3rd atom |
---|---|---|---|
1 | 1 | 2 | 3 |
2 | 2 | 4 | 5 |
Rat DHODH | Mouse DHODH | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
All analogues | Aromatic substituted analogues | Side chain 3-substituted analogues | All analogues | Aromatic substituted analogues | Side chain 3-substituted analogues | |||||||
Align. | 1 | 2 | 1 | 2 | 1 | 2 | 1 | 2 | 1 | 2 | 1 | 2 |
r2 | 0.658 | 0.687 | 0.758 | 0.665 | 0.778 | 0.897 | 0.517 | 0.572 | 0.554 | 0.657 | 0.697 | 0.859 |
rCV2 | 0.636 | 0.664 | 0.739 | 0.641 | 0.715 | 0.865 | 0.485 | 0.545 | 0.516 | 0.620 | 0.610 | 0.822 |
F | 98.428 | 112.251 | 125.687 | 79.723 | 35.180 | 87.269 | 52.608 | 65.608 | 47.310 | 72.892 | 23.106 | 61.314 |
s | 0.651 | 0.623 | 0.528 | 0.621 | 0.604 | 0.412 | 0.657 | 0.619 | 0.628 | 0.551 | 0.590 | 0.402 |
c1 | 0.695 | 0.766 | 0.650 | 0.769 | 0.800 | 0.987 | 0.531 | 0.625 | 0.429 | 0.660 | 0.934 | 0.918 |
rpred2 | 0.818 | 0.717 | 0.571 | 0.549 | 0.972 | 0.981 | 0.657 | 0.679 | 0.512 | 0.693 | 0.993 | 0.991 |
Compd | Rat DHODH | Mouse DHODH | ||||
---|---|---|---|---|---|---|
log(1/IC50) | log(1/IC50) | |||||
Observed | Predicted | Residuala | Observed | Predicted | Residuala | |
1 | 5.699 | 5.846 | −0.146 | 5.801 | 5.888 | −0.088 |
2 | 6.631 | 6.454 | 0.175 | 6.541 | 6.182 | 0.358 |
3 | 7.678 | 7.783 | −0.103 | 7.328 | 7.385 | −0.055 |
4 | 6.320 | 6.873 | −0.553 | 6.280 | 6.545 | −0.265 |
6 | 6.465 | 6.772 | −0.312 | 5.523 | 6.447 | −0.927 |
7 | 4.876 | 5.421 | −0.541 | 4.780 | 5.501 | −0.721 |
8 | 7.102 | 6.474 | 0.625 | 7.444 | 6.336 | 1.103 |
9 | 7.276 | 7.383 | −0.103 | 7.377 | 7.114 | 0.265 |
11 | 8.301 | 8.067 | 0.232 | 7.000 | 6.723 | 0.277 |
12 | 7.796 | 6.736 | 1.063 | 6.380 | 5.957 | 0.422 |
13 | 8.523 | 8.018 | 0.501 | 7.051 | 6.885 | 0.164 |
14 | 7.886 | 7.509 | 0.380 | 6.352 | 6.350 | −0.002 |
16 | 6.801 | 6.923 | −0.124 | 4.821 | 6.026 | −1.206 |
17 | 8.301 | 7.754 | 0.545 | 6.762 | 6.681 | 0.079 |
18 | 6.730 | 6.254 | 0.475 | 5.429 | 5.684 | −0.254 |
19 | 5.100 | 6.006 | −0.906 | − | − | − |
21 | 4.660 | 5.428 | −0.768 | 4.500 | 5.275 | −0.776 |
22 | 7.167 | 5.759 | 1.410 | 5.420 | 5.450 | −0.030 |
23 | 4.851 | 5.292 | −0.442 | − | − | − |
24 | 5.830 | 6.012 | −0.182 | 5.429 | 5.703 | −0.273 |
26 | 7.854 | 7.290 | 0.559 | 7.260 | 6.698 | 0.561 |
27 | 7.398 | 7.617 | −0.217 | 7.149 | 6.984 | 0.165 |
28 | 7.959 | 8.423 | −0.463 | 6.550 | 7.119 | −0.567 |
29 | 7.4819 | 7.104 | 0.375 | 7.400 | 6.697 | 0.703 |
31 | 7.1029 | 7.043 | 0.056 | 6.550 | 6.543 | 0.007 |
32 | 7.3019 | 7.260 | 0.039 | 7.201 | 6.813 | 0.387 |
33 | 7.553 | 6.803 | 0.746 | 7.444 | 6.875 | 0.564 |
34 | 7.959 | 7.718 | 0.241 | 6.750 | 6.729 | 0.021 |
36 | 6.200 | 6.092 | 0.107 | 5.599 | 5.299 | 0.300 |
37 | 6.530 | 6.312 | 0.217 | 6.201 | 5.678 | 0.521 |
38 | 6.229 | 7.021 | −0.791 | 6.250 | 6.438 | −0.188 |
39 | 4.750 | 5.469 | −0.720 | 5.301 | 5.380 | −0.081 |
41 | 5.670 | 5.640 | 0.030 | 5.070 | 5.090 | −0.020 |
42 | 5.830 | 6.735 | −0.905 | 5.801 | 5.856 | −0.055 |
43 | 7.886 | 7.906 | −0.016 | 7.161 | 7.431 | −0.270 |
44 | 6.550 | 6.402 | 0.147 | 6.680 | 6.274 | 0.406 |
46 | 4.750 | 5.791 | −1.041 | 4.932 | 5.664 | −0.732 |
47 | 4.350 | 5.299 | −0.950 | 5.100 | 5.488 | −0.388 |
48 | 6.530 | 6.261 | 0.268 | 7.036 | 6.210 | 0.826 |
49 | 6.600 | 6.371 | 0.229 | 6.710 | 6.276 | 0.434 |
51 | 6.301 | 6.505 | −0.205 | 5.680 | 6.153 | −0.473 |
52 | 5.851 | 6.039 | −0.189 | 5.370 | 5.743 | −0.373 |
Compd | Rat DHODH | Mouse DHODH | ||||
---|---|---|---|---|---|---|
log(1/IC50) | log(1/IC50) | |||||
Observed | Predicted | Residuala | Observed | Predicted | Residuala | |
5 | 7.201 | 6.882 | 0.318 | 7.444 | 6.569 | 0.871 |
10 | 5.343 | 6.928 | −1.588 | 4.429 | 6.185 | −1.755 |
15 | 6.080 | 7.117 | −1.037 | 4.650 | 6.340 | −1.690 |
20 | 7.678 | 7.376 | 0.304 | 7.301 | 6.998 | 0.302 |
25 | 6.801 | 6.593 | 0.207 | 5.951 | 6.084 | −0.134 |
30 | 5.903 | 5.710 | 0.190 | 5.429 | 5.794 | −0.364 |
35 | 7.745 | 8.034 | −0.294 | 6.750 | 6.847 | −0.097 |
40 | 6.750 | 6.632 | 0.118 | 6.201 | 5.895 | 0.305 |
45 | 4.500 | 5.313 | −0.813 | 4.550 | 5.392 | −0.842 |
50 | 7.638 | 6.461 | 1.179 | 6.750 | 6.086 | 0.664 |
53 | 6.971 | 6.298 | 0.672 | 7.201 | 6.174 | 1.026 |
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Li, S.-L.; He, M.-Y.; Du, H.-G. 3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide. Int. J. Mol. Sci. 2011, 12, 2982-2993. https://doi.org/10.3390/ijms12052982
Li S-L, He M-Y, Du H-G. 3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide. International Journal of Molecular Sciences. 2011; 12(5):2982-2993. https://doi.org/10.3390/ijms12052982
Chicago/Turabian StyleLi, Shun-Lai, Mao-Yu He, and Hong-Guang Du. 2011. "3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide" International Journal of Molecular Sciences 12, no. 5: 2982-2993. https://doi.org/10.3390/ijms12052982
APA StyleLi, S.-L., He, M.-Y., & Du, H.-G. (2011). 3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide. International Journal of Molecular Sciences, 12(5), 2982-2993. https://doi.org/10.3390/ijms12052982