W. Li et al./ Bioorg. Med. Chem. 14(2006)601-610 Table 2. CoMFA and CoMSIA analysis on indolomorphinan K antagonists SEEks Pred. r 0.238 0.188 0.607 CoMSIA(steric 0.217 0.150 0.579 CoMSIA(steric 0.286 50.707 0.228 0.886 CoMSIA(steric hydrophobic donor) 0.6033 0.840 0.294 0.627 CoMSIA(steric +electro hydrophobic acceptor) 0.620 6 0.961 0.155 97.745 0.108 0.980 0.45l 0.9040.233 6.16 Pred CoMSIA)predictive g values on the test se Table 3. Actual versus conventional fit values(predicted values)activities of CoMFA(standard) and CoMSIA (all descriptors) models on the aining set(test set) Actual pk CoMFa CoMSIA Conventional fit.c Conventional fit Res Mo molecule. 8.848 8.837 0.011 8.943 -0.095 Molecule-2 8.618 0.20 -0.271 Molecule- 3 8.670 0.158 -0.249 Molecule-4 0.012 219 Molecule- 6 Molecule-& Molecule. 9 -0.393 0.238 Molecule. 10 8.834 8.673 -O111 Molecule. 11 9.310 9.315 9.155 0.155 Molecule- 13 8.157 l57 0.000 -0.264 8.446 0.119 8.481 Molecule- 15 8.596 0.02 0.114 Molecule.17 8.804 9.084 -0.280 8978 -0.174 Molecule- 18 -0.067 9.042 Molecule.19 9.214 -0.046 Molecule- 20 9.538 8.997 0.541 9.223 315 Molecule-2 9.266 9.39 Molecule- 23 9.359 9.460 Molecule- 24 8.857 9.156 04 Molecule- 26 0.02 8.175 0.024 Molecule- 27 8.031 0.059 7.962 0.128 Molecule- 29 8.842 8.645 0.133 Molecule.30 -0.307 0.420 Molecule.31 7.722 7.759 Molecule.32 0.415 8.172 -0.186 Molecule- 34 0.128 Molecule. 35 8.676 0.175 8.384 0.292 Molecule- 36 8.135 Molecule. 38 6.738 0.022 Molecule- 39 6.670 (b) Test set OMA b CoMSIA ctual pk Predicted pKi -0.150 8.547 0.246 8.677 -0.358 8.549 -0.142 0.218 1583 8.656 6.743 0.178 CoMSIA model combined with all descriptors cOnventional fitted value Difference between actual and fitted (predicted) pki values Predicted pKi valuTable 3. Actual versus conventional fit values (predicted values) activities of CoMFA (standard) and CoMSIA (all descriptors) models on the training set (test set) Compound Actual pKi CoMFAa CoMSIAb Conventional fit.c Resd Conventional fitc Resd (a) Training set Molecule-1 8.848 8.837 0.011 8.943
0.095 Molecule-2 8.618 8.826
0.208 8.889
0.271 Molecule-3 8.670 8.828
0.158 8.919
0.249 Molecule-4 9.022 8.867 0.155 9.034
0.012 Molecule-5 9.066 8.847 0.219 8.796 0.270 Molecule-6 9.181 8.967 0.214 8.802 0.379 Molecule-8 9.201 8.947 0.254 8.922 0.279 Molecule-9 8.487 8.880
0.393 8.725
0.238 Molecule-10 8.562 8.834
0.272 8.673
0.111 Molecule-11 9.310 9.315
0.005 9.155 0.155 Molecule-13 8.157 8.157 0.000 8.421
0.264 Molecule-14 8.565 8.446 0.119 8.481 0.084 Molecule-15 8.623 8.596 0.027 8.509 0.114 Molecule-17 8.804 9.084
0.280 8.978
0.174 Molecule-18 9.071 9.138
0.067 9.042 0.029 Molecule-19 9.168 9.214
0.046 9.108 0.059 Molecule-20 9.538 8.997 0.541 9.223 0.315 Molecule-22 9.602 9.266 0.336 9.391 0.211 Molecule-23 9.523 9.359 0.164 9.460 0.063 Molecule-24 8.857 9.156
0.299 9.331
0.474 Molecule-26 8.199 8.221
0.022 8.175 0.024 Molecule-27 8.090 8.031 0.059 7.962 0.128 Molecule-29 8.842 8.645 0.197 8.709 0.133 Molecule-30 8.251 8.558
0.307 8.671
0.420 Molecule-31 7.660 7.722
0.062 7.759
0.099 Molecule-32 7.986 8.401
0.415 8.172
0.186 Molecule-34 8.209 8.218
0.009 8.081 0.128 Molecule-35 8.676 8.501 0.175 8.384 0.292 Molecule-36 7.996 8.100
0.104 8.135
0.139 Molecule-38 6.738 6.635 0.103 6.715 0.022 Molecule-39 6.719 6.642 0.077 6.670 0.049 (b) Test set CoMFAa CoMSIAb Compound Actual pKi Predicted pKi e Resd Predicted pKi e Resd Molecule-7 8.793 8.943
0.150 8.547 0.246 Molecule-12 8.319 8.659
0.340 8.677
0.358 Molecule-16 8.408 8.806
0.398 8.549
0.142 Molecule-21 9.553 9.180 0.373 9.335 0.218 Molecule-25 7.909 8.671
0.761 8.415
0.505 Molecule-28 8.796 8.537 0.259 8.675 0.121 Molecule-33 8.656 7.977 0.679 7.832 0.824 Molecule-37 6.921 6.630 0.291 6.743 0.178 a CoMFA standard model. b CoMSIA model combined with all descriptors. c Conventional fitted value. d Difference between actual and fitted (predicted) pKi values. e Predicted pKi value. Table 2. CoMFA and CoMSIA analysis on indolomorphinan j antagonists Model q2 N r2 SEE F SEEbs q2 bs Pred. r 2 CoMFA(std) 0.693 4 0.900 0.238 58.245 0.188 0.924 0.607 CoMSIA(steric + electro) 0.738 6 0.923 0.217 47.651 0.150 0.964 0.579 CoMSIA(steric + electro + hydrophobic) 0.591 3 0.849 0.286 50.707 0.228 0.886 0.603 CoMSIA(steric + electro + hydrophobic + donor) 0.603 3 0.840 0.294 47.372 0.234 0.895 0.627 CoMSIA(steric + electro + hydrophobic + acceptor) 0.620 6 0.961 0.155 97.745 0.108 0.980 0.451 CoMSIA(all descriptors) 0.617 4 0.904 0.233 61.168 0.198 0.886 0.701 q2 —leave one out (LOO) cross-validated correlation coefficient, N—optimum number of components, r 2 —noncross-validated correlation coefficient, SEE—standard error of estimate, F—F-test value, SEEbs—standard error of estimate by boot strapping analysis, q2 bs—mean r 2 by boot strapping analysis (in 10 runs), Pred. r 2 —CoMFA (CoMSIA) predictive q2 values on the test set. 606 W. Li et al. / Bioorg. Med. Chem. 14 (2006) 601–610