Table 1S. The chemical structures and biological activity values of the studied inhibitors (Chen et al. 2012; Chen et al. 2011; Harper et al. 2005).
Number / R1 / R2 / R3 / pIC50m1 / H / Cl / H / 7.275
m2* / Cl / Cl / H / 6.125
m3 / Br / H / H / 5.398
m4 / H / Cl / Cl / 7.328
m5* / H / Br / H / 7.356
m6* / H / / H / 5.155
m7 / H / / H / 5.854
m8 / H / / H / 6.481
m9 / H / OH / H / 4.699
m10 / H / CF3 / H / 7.769
Table 1S. Continued…
Number / R4 / pIC50 / Number / R2 / pIC50
m11 / / 7.602 / m20 / / 7.619
m12 / / 7.173 / m21 / / 7.823
m13 / / 8.045 / m22 / / 7.102
m14 / / 8.045 / m23 / Me / 8.096
m15 / / 7.795 / m24 / / 8.397
m16 / / 7.602 / m25 / Br / 8.522
m17 / / 8.301 / m26 / / 8.096
m18 / / 8.397 / m27* / / 8.096
m19 / / 8.154 / m28 / / 8.045
Table 1S. Continued…
Number / R2 / R5 / pIC50m29 / Me / Me / 8.155
m30 / / 8
m31* / / 8.154
m32* / / 8.221
m33 / Et / Me / 8.222
m34 / / 8.221
m35* / / 8.301
m36* / / 8.522
Table 1S. Continued…
Number / R2 / R3 / pIC50m37 / CF3 / H / 8.523
m38* / / H / 8.221
m39* / / H / 8.222
m40 / / H / 8.155
m41 / Me / F / 8.097
m42 / Me / Cl / 8.301
m43 / Me / CF3 / 8.154
m44* / CF3 / F / 8.155
m45 / / F / 8.301
Table 1S. Continued…
Number / X / pIC50 / Number / X / pIC50m46 / / 7.207 / m54 / / 7.958
m47 / / 7.200 / m55 / / 8.096
m48 / / 7.008 / m56 / / 7.769
m49 / / 7.366 / m57 / / 7.958
m50 / / 7.721 / m58 / / 8.155
m51* / / 7.148 / m59* / / 7.886
m52 / / 7.408 / m60 / / 7.921
m53 / / 7.744 / m61 / / 7.920
Table 1S. Continued…
Number / X / pIC50 / Number / X / pIC50m62 / / 6.612 / m65* / / 7.167
m63 / / 6.349 / m66 / / 7.328
m64 / / 7.108
Table 1S. Continued…
Number / Ar / pIC50 / Number / Ar / pIC50m69 / / 6.479 / m74 / / 6.832
m70 / / 6.873 / m75 / / 7.107
m71 / / 7.161 / m76 / / 7.108
m72 / / 7.509 / m77 / / 7.744
m73 / / 6.036 / m78 / / 8.301
Number / pIC50
m67 / / 7.143
m68* / / 7.229
Table 1S. Continued…
Number / X / pIC50 / Number / X / pIC50m79* / / 8.398 / m88 / / 7.854
m80 / / 8.222 / m89 / / 8.699
m81 / / 8.046 / m90† / / 8.523
m82 / / 8.398 / m91† / / 8.222
m83 / / 8.301 / m92† / / 7.854
m84 / / 8.155 / m93 / / 8.301
m85 / / 8.523 / m94* / / 8.222
m86 / / 7.337 / m95 / / 8.523
m87 / / 7.854 / An †denotes that the C5 substituent was an ethyl group for these inhibitors.
Table 1S. Continued…
Number / R3 / R2 / pIC50 / Number / R3 / R2 / pIC50
m96 / H / / 8.222 / m100 / H / / 8.301
m97* / H / / 8.222 / m101 / Me / / 7.886
m98* / H / / 8.398 / m102* / Me / / 8.222
m99 / H / / 8.155 / m103 / Me / / 7.921
Table 1S. Continued…
Number / R5 / R6 / pIC50m104 / F / H / 8.301
m105 / H / H / 8.398
m106* / Cl / H / 8.222
m107 / CF3 / H / 8.398
m108 / t-Bu / H / 8.221
m109* / Et / H / 8.398
m110 / Me / F / 8.155
Table 2S. Measured and predicted pIC50 and residual values of training set.
compound / MeasuredpIC50 / GA-SVM / GA-PLS / CoMFA
predicted / residual / predicted / residual / predicted / residual
m1 / 7.276 / 7.202 / -0.073 / 7.218 / -0.057 / 7.388 / 0.112
m3 / 5.398 / 5.471 / 0.073 / 5.644 / 0.246 / 5.295 / -0.103
m4 / 7.328 / 7.437 / 0.109 / 7.461 / 0.133 / 7.269 / -0.059
m7 / 5.854 / 6.964 / 1.110 / 6.847 / 0.993 / 5.744 / -0.110
m8 / 6.481 / 6.408 / -0.073 / 6.417 / -0.064 / 6.048 / -0.433
m9 / 4.699 / 5.998 / 1.299 / 5.953 / 1.254 / 4.784 / 0.085
m10 / 7.770 / 7.303 / -0.467 / 7.326 / -0.443 / 8.060 / 0.290
m11 / 7.602 / 7.532 / -0.070 / 7.550 / -0.052 / 7.657 / 0.055
m12 / 7.174 / 7.371 / 0.198 / 7.434 / 0.260 / 7.726 / 0.552
m13 / 8.046 / 7.784 / -0.262 / 7.838 / -0.208 / 7.867 / -0.179
m14 / 8.046 / 8.267 / 0.222 / 8.129 / 0.083 / 7.974 / -0.072
m15 / 7.796 / 7.735 / -0.061 / 7.785 / -0.010 / 7.684 / -0.112
m16 / 7.602 / 8.317 / 0.715 / 8.207 / 0.605 / 7.942 / 0.340
m17 / 8.301 / 8.184 / -0.117 / 8.030 / -0.271 / 8.242 / -0.059
m18 / 8.398 / 8.326 / -0.072 / 8.207 / -0.191 / 8.219 / -0.179
m19 / 8.155 / 7.854 / -0.301 / 7.705 / -0.450 / 8.076 / -0.079
m20 / 7.620 / 7.791 / 0.171 / 7.703 / 0.083 / 7.784 / 0.164
m21 / 7.824 / 7.639 / -0.185 / 7.501 / -0.322 / 7.744 / -0.080
m22 / 7.102 / 7.615 / 0.513 / 7.480 / 0.378 / 7.345 / 0.243
m23 / 8.097 / 8.101 / 0.004 / 7.918 / -0.179 / 8.100 / 0.003
m24 / 8.398 / 8.018 / -0.379 / 7.826 / -0.572 / 8.222 / -0.176
m25 / 8.523 / 8.596 / 0.073 / 8.644 / 0.121 / 8.357 / -0.166
m26 / 8.097 / 8.024 / -0.073 / 7.886 / -0.211 / 8.135 / 0.038
m28 / 8.046 / 7.916 / -0.130 / 7.734 / -0.312 / 7.903 / -0.143
m29 / 8.155 / 8.254 / 0.099 / 8.455 / 0.300 / 8.091 / -0.064
m30 / 8.000 / 8.202 / 0.202 / 8.376 / 0.376 / 8.123 / 0.123
m33 / 8.222 / 8.186 / -0.036 / 8.359 / 0.137 / 8.256 / 0.034
m34 / 8.222 / 8.227 / 0.005 / 8.405 / 0.183 / 8.237 / 0.015
m37 / 8.523 / 8.139 / -0.384 / 8.260 / -0.263 / 8.423 / -0.100
m40 / 8.222 / 8.149 / -0.073 / 8.293 / 0.071 / 8.243 / 0.021
m41 / 8.097 / 8.245 / 0.148 / 8.507 / 0.410 / 8.184 / 0.087
m42 / 8.301 / 8.401 / 0.099 / 8.571 / 0.270 / 8.096 / -0.205
m43 / 8.155 / 8.036 / -0.119 / 8.130 / -0.025 / 8.082 / -0.073
m45 / 8.301 / 8.228 / -0.073 / 8.473 / 0.172 / 8.217 / -0.084
m46 / 7.208 / 7.224 / 0.017 / 7.213 / 0.005 / 7.288 / 0.080
m47 / 7.201 / 7.339 / 0.138 / 7.335 / 0.134 / 7.230 / 0.029
m48 / 7.009 / 7.283 / 0.274 / 7.135 / 0.126 / 6.936 / -0.073
m49 / 7.367 / 7.509 / 0.143 / 7.976 / 0.610 / 7.457 / 0.090
m50 / 7.721 / 7.648 / -0.073 / 7.655 / -0.067 / 7.532 / -0.189
m52 / 7.409 / 7.185 / -0.224 / 7.055 / -0.354 / 7.180 / -0.229
m53 / 7.745 / 6.976 / -0.769 / 6.917 / -0.828 / 7.576 / -0.169
m54 / 7.959 / 7.808 / -0.151 / 7.949 / -0.010 / 7.477 / -0.482
m55 / 8.097 / 8.037 / -0.060 / 8.188 / 0.092 / 8.087 / -0.010
m56 / 7.770 / 7.864 / 0.095 / 7.831 / 0.061 / 7.764 / -0.006
m57 / 7.959 / 7.885 / -0.073 / 8.193 / 0.235 / 7.967 / 0.008
m58 / 8.155 / 8.227 / 0.072 / 8.251 / 0.096 / 8.213 / 0.058
m60 / 7.921 / 7.848 / -0.073 / 7.848 / -0.073 / 8.035 / 0.114
m61 / 7.921 / 7.618 / -0.303 / 7.662 / -0.259 / 8.092 / 0.171
m62 / 6.613 / 6.686 / 0.073 / 6.726 / 0.114 / 6.497 / -0.116
m63 / 6.349 / 6.751 / 0.403 / 6.795 / 0.446 / 6.205 / -0.144
m64 / 7.108 / 7.181 / 0.073 / 7.050 / -0.058 / 7.207 / 0.099
m66 / 7.328 / 7.061 / -0.267 / 6.994 / -0.334 / 7.446 / 0.118
m67 / 7.143 / 6.995 / -0.148 / 6.936 / -0.206 / 7.428 / 0.285
m69 / 6.479 / 6.877 / 0.398 / 6.832 / 0.353 / 6.901 / 0.422
m70 / 6.873 / 7.090 / 0.217 / 7.023 / 0.150 / 6.871 / -0.002
m71 / 7.161 / 6.845 / -0.316 / 6.763 / -0.398 / 6.958 / -0.203
m72 / 7.509 / 6.875 / -0.634 / 6.814 / -0.695 / 7.209 / -0.300
m73 / 6.036 / 6.789 / 0.753 / 6.736 / 0.700 / 6.255 / 0.219
m74 / 6.833 / 6.992 / 0.160 / 6.933 / 0.100 / 6.983 / 0.150
m75 / 7.108 / 7.462 / 0.355 / 7.519 / 0.411 / 7.431 / 0.323
m76 / 7.108 / 7.009 / -0.099 / 6.953 / -0.155 / 7.036 / -0.072
m77 / 7.745 / 6.944 / -0.801 / 6.999 / -0.746 / 7.512 / -0.233
m78 / 8.301 / 8.224 / -0.077 / 8.439 / 0.138 / 8.235 / -0.066
m80 / 8.222 / 7.859 / -0.363 / 7.668 / -0.553 / 8.291 / 0.069
m81 / 8.046 / 8.010 / -0.036 / 8.065 / 0.019 / 8.058 / 0.012
m82 / 8.398 / 7.915 / -0.483 / 7.854 / -0.544 / 8.164 / -0.234
m83 / 8.301 / 8.374 / 0.073 / 8.421 / 0.120 / 8.296 / -0.005
m84 / 8.301 / 8.374 / 0.073 / 8.243 / -0.058 / 8.349 / 0.048
m85 / 8.523 / 8.269 / -0.254 / 8.032 / -0.491 / 8.538 / 0.015
m86 / 7.337 / 7.767 / 0.430 / 7.623 / 0.285 / 7.445 / 0.108
m87 / 7.854 / 7.889 / 0.035 / 7.834 / -0.020 / 7.964 / 0.110
m88 / 7.854 / 8.287 / 0.433 / 8.428 / 0.574 / 7.839 / -0.015
m89 / 8.699 / 8.306 / -0.393 / 8.365 / -0.334 / 8.379 / -0.320
m90 / 8.523 / 8.596 / 0.073 / 8.506 / -0.017 / 8.462 / -0.061
m91 / 8.222 / 8.024 / -0.198 / 7.630 / -0.592 / 8.149 / -0.073
m92 / 7.854 / 7.927 / 0.073 / 7.955 / 0.101 / 7.786 / -0.068
m93 / 8.155 / 8.082 / -0.073 / 7.831 / -0.324 / 8.133 / -0.022
m95 / 8.523 / 8.015 / -0.508 / 7.976 / -0.547 / 8.302 / -0.221
m96 / 8.222 / 8.365 / 0.143 / 8.434 / 0.212 / 8.352 / 0.130
m99 / 8.155 / 8.111 / -0.044 / 8.171 / 0.016 / 8.232 / 0.077
m100 / 8.301 / 8.156 / -0.145 / 7.911 / -0.390 / 8.531 / 0.230
m101 / 7.886 / 7.959 / 0.073 / 7.906 / 0.020 / 8.058 / 0.172
m103 / 7.921 / 8.297 / 0.376 / 8.282 / 0.361 / 8.398 / 0.477
m104 / 8.301 / 8.228 / -0.073 / 8.602 / 0.301 / 8.166 / -0.135
m105 / 8.398 / 8.325 / -0.073 / 8.381 / -0.017 / 8.253 / -0.145
m107 / 8.398 / 8.122 / -0.276 / 7.995 / -0.403 / 8.344 / -0.054
m108 / 8.222 / 8.301 / 0.079 / 8.248 / 0.026 / 8.063 / -0.159
m110 / 8.155 / 8.245 / 0.090 / 8.377 / 0.222 / 8.220 / 0.065
Table 3S. Measured and predicted pIC50 and residual values of test set.
compound / MeasuredpIC50 / SVM / PLS / CoMFA
predicted / residual / predicted / residual / predicted / residual
m2 / 6.125 / 6.600 / 0.475 / 6.620 / 0.495 / 6.376 / 0.251
m5 / 7.357 / 7.507 / 0.150 / 7.759 / 0.403 / 6.909 / -0.448
m6 / 5.155 / 5.948 / 0.793 / 5.839 / 0.684 / 5.158 / 0.003
m27 / 8.097 / 7.939 / -0.158 / 7.691 / -0.406 / 7.557 / -0.540
m31 / 8.155 / 8.161 / 0.007 / 8.309 / 0.154 / 7.847 / -0.308
m32 / 8.222 / 8.182 / -0.040 / 8.436 / 0.214 / 8.373 / 0.151
m35 / 8.301 / 8.143 / -0.158 / 8.575 / 0.274 / 7.850 / -0.451
m36 / 8.523 / 8.168 / -0.354 / 8.319 / -0.204 / 8.604 / 0.081
m38 / 8.222 / 8.131 / -0.091 / 8.256 / 0.034 / 8.222 / 0.000
m39 / 8.222 / 8.133 / -0.089 / 8.222 / 0.000 / 7.980 / -0.242
m44 / 8.155 / 8.170 / 0.015 / 8.507 / 0.352 / 8.589 / 0.434
m51 / 7.149 / 7.101 / -0.048 / 6.687 / -0.462 / 7.589 / 0.440
m59 / 7.886 / 7.875 / -0.011 / 7.973 / 0.087 / 7.415 / -0.471
m65 / 7.167 / 7.252 / 0.085 / 6.816 / -0.351 / 7.110 / -0.057
m68 / 7.229 / 7.429 / 0.200 / 7.137 / -0.093 / 7.364 / 0.135
m79 / 8.398 / 8.187 / -0.211 / 8.376 / -0.022 / 8.391 / -0.007
m94 / 8.222 / 8.308 / 0.086 / 8.340 / 0.118 / 8.753 / 0.531
m97 / 8.222 / 8.308 / 0.086 / 8.440 / 0.218 / 8.278 / 0.056
m98 / 8.398 / 8.293 / -0.105 / 8.296 / -0.102 / 7.759 / -0.639
m102 / 8.222 / 8.317 / 0.095 / 8.369 / 0.147 / 8.624 / 0.402
m106 / 8.222 / 8.324 / 0.102 / 8.274 / 0.052 / 8.598 / 0.376
m109 / 8.398 / 8.302 / -0.096 / 8.301 / -0.097 / 8.081 / -0.317
Figure 1S. The predicted versus measured pIC50 values of CoMFA model.
Figure 2S. CoMFA StDev*Coeff. contour plots. Steric contour map for m22. Green contours indicate regions where bulky groups increase activity (favored level 80%), and yellow contours indicate regions where bulky groups decrease activity (disfavored level 20%). (B) Electrostatic contour maps for m22. Red contours indicate regions where negative charges increase activity (disfavored level 20%), and blue contours indicate regions where positive charges increase activity (favored level 80%).