Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Multiple Structure Alignment Analyses
2.2. CoMFA and CoMSIA Statistical Results
2.3. CoMFA Contour Maps
2.4. CoMSIA Contour Maps
2.5. Comparison of Pharmacophore Model and CoMSIA Model
2.6. Structural Insights from 3D-QSAR and Pharmacophore Studies
3. Materials and Methods
3.1. Dataset
3.2. Conformational Alignment
3.2.1. Common Substructure Based Alignment
3.2.2. Molecular Docking Based Alignment
3.2.3. Pharmacophore Based Alignment
3.3. CoMFA and CoMSIA Methodology
3.4. Partial Least Squared (PLS) Analyses and Validation
4. Conclusions
Acknowledgments
References
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Compound | R1 | R2 | R3 | R4 |
---|---|---|---|---|
1 * | NHMe | Me | H | H |
2 * | NHcyclopropyl | Me | H | H |
3 | NHcyclopentyl | Me | H | H |
4 | NHPh | Me | H | H |
5 | NH2 | Me | CF3 | H |
6 | NH2 | Ph | H | H |
7 | NH2 | i-Pr | H | H |
8 | NH2 | 1-methylpiperidine-4-yl | H | H |
9 | NH2 | 2-(piperidin-1-yl)-ethyl | H | H |
10* | NH2 | Me | H | m-CF3 |
11 | NH2 | Me | H | p-CF3 |
12 | NH2 | Me | Ac | H |
13 | NH2 | Me | H | m-Ac |
14 | NH2 | Me | OMe | H |
15 | NH2 | Me | H | m-OMe |
16 | NH2 | Me | H | p-OMe |
17 | NH2 | Me | NO2 | H |
18 | NH2 | Me | H | m-NO2 |
19 | NH2 | Me | Me | H |
20 * | NH2 | Me | NHMe | H |
21 | NH2 | Me | i-Pr | H |
22 * | NH2 | Me | COOMe | H |
23 * | NH2 | Me | CONH2 | H |
24 | NH2 | Me | SO2NH2 | H |
25 | NH2 | Me | Ph | H |
26 * | NH2 | Me | OPh | H |
27 | NH2 | Me | benzyl | H |
28 * | NH2 | Me | NHPh | H |
29 | NH2 | Me | benzoyl | H |
30 * | NH2 | Me | SPh | H |
31 | NH2 | Me | Ac | 3′-(4-methyl-piperazin-1-yl) |
32 * | NH2 | Me | Ac | 4′-(4-methyl-piperazin-1-yl) |
33 | NH2 | Me | Ac | 5′-(4-methyl-piperazin-1-yl) |
34 | NH2 | Me | OMe | 4′-(4-methyl-piperazin-1-yl) |
35 * | NH2 | Me | OMe | 5′-(4-methyl-piperazin-1-yl) |
36 | OEt | Me | H | H |
37 | NH2 | Me | NH2 | H |
38 | NH2 | Me | NHAc | H |
39 | NH2 | Me | OCF3 | H |
40 | NH2 | Me | OCF3 | |
41 * | NH2 | Me | OCF3 | |
42 | NH2 | Me | OCF3 | |
43 | NH2 | Me | OCF3 | |
44 | NH2 | Me | OCF3 | |
45 | NH2 | Me | OCF3 | |
46 * | NH2 | Trityl | OCF3 | |
47 | NH2 | H | OCF3 | |
48 * | NH2 | 2-Fluoro-ethyl | OCF3 | |
49 | NH2 | Ethyl | OCF3 | |
50 * | NH2 | 2-Methoxy-ethyl | OCF3 | |
51 | NH2 | 2-Chloro-ethyl | OCF3 | |
52 | NH2 | Vinyl | OCF3 | |
53 * | NH2 | Me | OCF3 | |
54 | NH2 | Me | OCF3 | 5′-NH2 |
55 | NH2 | Me | OCF3 | |
56 * | NH2 | Me | OCF3 | |
57 | NH2 | Me | OCF3 | |
58 | NH2 | Me | OCF3 | |
59 | NH2 | Me | OCF3 | |
60 | NH2 | Me | OCF3 | |
61 | NH2 | Me | OCF3 | |
62 * | NH2 | Me | OCF3 | |
63 | NH2 | Me | OCF3 | |
64 * | NH2 | Me | OCF3 | |
65 | NH2 | Me | OCF3 | |
66 * | NH2 | Me | OCF3 | |
67 | NH2 | Me | OCF3 | |
68 | NH2 | Me | OCF3 | |
69 | NH2 | −(CH2)3–N–(CH3)2 | OCF3 | |
70 * | NH2 | OCF3 | ||
71 | NH2 | − (CH2)2–NH2 | OCF3 | |
72 | NH2 | − (CH2)3–NH2 | OCF3 | |
73 | NH2 | − (CH2)2–OH | OCF3 |
Alignment Method | CoMFA Model | CoMSIA Model | ||||
---|---|---|---|---|---|---|
GD a | PH b | CS c | GD | PH | CS | |
No. | 1 | 2 | 3 | 4 | 5 | 6 |
q2 | 0.283 | 0.628 | 0.578 | 0.574 | 0.532 | 0.588 |
r2 | 0.42 | 0.941 | 0.867 | 0.97 | 0.859 | 0.834 |
SEE d | 0.818 | 0.268 | 0.404 | 0.198 | 0.411 | 0.447 |
F e | 36.929 | 192.635 | 78.313 | 207.094 | 99.622 | 81.965 |
ONC f | 1 | 4 | 4 | 7 | 3 | 3 |
Field analysis | ||||||
Steric | 0.663 | 0.619 | 0.698 | 0.177 | 0.224 | 0.263 |
Electrostatic | 0.337 | 0.381 | 0.618 | 0.52 | 0.407 | 0.459 |
Hydrophobic | - | - | - | - | - | - |
H-bond donor | - | - | - | 0.303 | 0.369 | 0.277 |
H-bond acceptor | - | - | - | - | - | - |
Test set | ||||||
r2pred g | 0.405 | 0.785 | 0.752 | 0.605 | 0.695 | 0.749 |
Compound | pIC50 | Model 1 | Model 2 | Model 3 | |||
---|---|---|---|---|---|---|---|
Prediction | Residue | Prediction | Residue | Prediction | Residue | ||
1 * | 5.375 | 5.848 | −0.473 | 5.227 | 0.148 | 5.380 | −0.005 |
2 * | 5.000 | 5.934 | −0.934 | 5.406 | −0.406 | 5.063 | −0.063 |
3 | 5.000 | 5.824 | −0.824 | 5.228 | −0.228 | 4.778 | 0.222 |
4 | 5.000 | 5.724 | −0.724 | 4.795 | 0.205 | 5.298 | −0.298 |
5 | 6.365 | 6.544 | −0.180 | 6.382 | −0.018 | 6.282 | 0.082 |
6 | 5.000 | 6.101 | −1.101 | 5.591 | −0.591 | 5.653 | −0.653 |
7 | 6.367 | 6.074 | 0.293 | 5.935 | 0.432 | 5.765 | 0.602 |
8 | 5.000 | 6.394 | −1.394 | 5.096 | −0.096 | 4.798 | 0.202 |
9 | 5.000 | 6.543 | −1.543 | 4.966 | 0.034 | 5.060 | −0.060 |
10 * | 7.292 | 6.249 | 1.043 | 7.358 | −0.066 | 6.423 | 0.869 |
11 | 6.060 | 5.547 | 0.513 | 6.153 | −0.093 | 6.165 | −0.106 |
12 | 6.461 | 6.536 | −0.075 | 6.401 | 0.060 | 6.286 | 0.175 |
13 | 7.000 | 5.914 | 1.086 | 7.105 | −0.105 | 6.575 | 0.425 |
14 | 7.377 | 6.378 | 0.999 | 7.359 | 0.018 | 7.120 | 0.257 |
15 | 6.870 | 6.068 | 0.802 | 6.798 | 0.072 | 6.649 | 0.221 |
16 | 6.592 | 5.970 | 0.622 | 6.402 | 0.190 | 6.886 | −0.294 |
17 | 6.312 | 6.354 | −0.042 | 6.395 | −0.083 | 6.125 | 0.187 |
18 | 5.000 | 5.892 | −0.892 | 5.074 | −0.074 | 6.189 | −1.189 |
19 | 7.824 | 6.040 | 1.784 | 7.420 | 0.404 | 6.858 | 0.966 |
20 * | 6.959 | 6.260 | 0.699 | 6.240 | 0.719 | 7.193 | −0.234 |
21 | 6.438 | 6.216 | 0.222 | 6.485 | −0.047 | 6.749 | −0.311 |
22 * | 5.952 | 6.490 | −0.538 | 6.844 | −0.892 | 6.745 | −0.793 |
23 * | 5.683 | 6.250 | −0.567 | 5.481 | 0.202 | 6.781 | −1.098 |
24 | 5.428 | 6.150 | −0.722 | 5.564 | −0.136 | 6.110 | −0.682 |
25 | 5.806 | 6.316 | −0.511 | 6.198 | −0.393 | 6.044 | −0.238 |
26 * | 6.556 | 6.624 | −0.068 | 6.279 | 0.277 | 6.216 | 0.340 |
27 | 6.026 | 6.216 | −0.191 | 6.005 | 0.021 | 6.035 | −0.010 |
28 * | 6.023 | 6.609 | −0.586 | 6.150 | −0.127 | 6.212 | −0.189 |
29 | 5.706 | 6.380 | −0.674 | 5.686 | 0.020 | 5.724 | −0.018 |
30 * | 5.692 | 6.772 | −1.080 | 6.168 | −0.476 | 6.094 | −0.402 |
31 | 5.688 | 5.964 | −0.276 | 5.904 | −0.216 | 5.913 | −0.225 |
32 * | 6.334 | 6.768 | −0.435 | 5.746 | 0.587 | 7.694 | −1.361 |
33 | 6.963 | 7.711 | −0.748 | 7.152 | −0.189 | 6.698 | 0.265 |
34 | 7.398 | 6.327 | 1.071 | 7.573 | −0.175 | 7.330 | 0.068 |
35 * | 8.155 | 7.441 | 0.714 | 8.503 | −0.348 | 8.226 | −0.071 |
36 | 5.000 | 5.874 | −0.874 | 5.070 | −0.070 | 5.195 | −0.195 |
37 | 6.824 | 6.153 | 0.671 | 6.920 | −0.096 | 6.796 | 0.028 |
38 | 5.598 | 5.973 | −0.375 | 5.145 | 0.453 | 5.588 | 0.010 |
39 | 6.932 | 6.387 | 0.545 | 6.681 | 0.251 | 6.716 | 0.216 |
40 | 6.016 | 7.373 | −1.357 | 6.026 | −0.010 | 5.755 | 0.261 |
41 * | 6.910 | 7.384 | −0.474 | 6.320 | 0.590 | 7.188 | −0.278 |
42 | 8.097 | 7.501 | 0.596 | 8.130 | −0.033 | 8.653 | −0.556 |
43 | 7.114 | 7.318 | −0.204 | 7.163 | −0.050 | 7.056 | 0.058 |
44 | 8.699 | 7.428 | 1.271 | 8.567 | 0.132 | 8.275 | 0.424 |
45 | 7.456 | 7.522 | −0.066 | 7.163 | 0.293 | 7.905 | −0.449 |
46 * | 5.000 | 7.379 | −2.379 | 5.528 | −0.528 | 4.123 | 0.877 |
47 | 8.398 | 7.156 | 1.242 | 8.361 | 0.037 | 8.363 | 0.035 |
48 * | 8.398 | 7.276 | 1.122 | 7.868 | 0.530 | 8.064 | 0.334 |
49 | 8.222 | 7.609 | 0.613 | 7.959 | 0.263 | 8.069 | 0.153 |
50 * | 7.824 | 7.300 | 0.524 | 7.527 | 0.297 | 7.675 | 0.149 |
51 | 8.155 | 7.316 | 0.839 | 8.152 | 0.003 | 7.918 | 0.237 |
52 | 8.222 | 7.518 | 0.704 | 8.339 | −0.117 | 8.073 | 0.149 |
53 * | 8.523 | 7.555 | 0.968 | 8.221 | 0.302 | 8.579 | −0.056 |
54 | 7.222 | 6.432 | 0.790 | 7.500 | −0.278 | 7.182 | 0.040 |
55 | 7.602 | 7.416 | 0.186 | 7.967 | −0.365 | 7.685 | −0.083 |
56 * | 7.482 | 7.453 | 0.028 | 6.750 | 0.732 | 8.656 | −1.175 |
57 | 6.699 | 7.505 | −0.806 | 7.303 | −0.604 | 6.568 | 0.131 |
58 | 8.523 | 7.497 | 1.026 | 8.082 | 0.441 | 8.499 | 0.024 |
59 | 8.222 | 7.333 | 0.889 | 8.070 | 0.152 | 8.018 | 0.204 |
60 | 6.813 | 7.516 | −0.704 | 6.580 | 0.233 | 7.415 | −0.603 |
61 | 6.697 | 7.502 | −0.805 | 6.439 | 0.258 | 7.358 | −0.661 |
62 * | 7.377 | 7.417 | −0.040 | 7.465 | −0.088 | 7.735 | −0.358 |
63 | 7.222 | 7.129 | 0.093 | 7.568 | −0.346 | 6.608 | 0.614 |
64 * | 6.975 | 7.354 | −0.379 | 6.220 | 0.755 | 7.077 | −0.102 |
65 | 6.827 | 7.660 | −0.833 | 6.591 | 0.236 | 7.034 | −0.207 |
66 * | 7.081 | 7.358 | −0.277 | 6.546 | 0.535 | 6.968 | 0.113 |
67 | 7.357 | 7.555 | −0.199 | 7.285 | 0.071 | 6.833 | 0.523 |
68 | 6.650 | 7.634 | −0.984 | 6.181 | 0.469 | 6.117 | 0.533 |
69 | 6.554 | 7.291 | −0.737 | 6.763 | −0.209 | 6.665 | −0.111 |
70 * | 7.367 | 7.521 | −0.155 | 6.587 | 0.780 | 7.756 | −0.390 |
71 | 7.482 | 7.562 | −0.081 | 8.013 | −0.532 | 7.765 | −0.284 |
72 | 7.284 | 7.647 | −0.363 | 7.332 | −0.048 | 7.703 | −0.419 |
73 | 8.699 | 7.541 | 1.158 | 8.292 | 0.407 | 8.235 | 0.464 |
Compound | pIC50 | Model 4 | Model 5 | Model 6 | |||
---|---|---|---|---|---|---|---|
Prediction | Residue | Prediction | Residue | Prediction | Residue | ||
1 * | 5.375 | 5.171 | 0.204 | 5.208 | 0.167 | 4.833 | 0.542 |
2 * | 5.000 | 5.524 | −0.524 | 5.168 | −0.168 | 4.781 | 0.219 |
3 | 5.000 | 5.037 | −0.037 | 5.159 | −0.159 | 4.620 | 0.380 |
4 | 5.000 | 5.099 | −0.099 | 5.024 | −0.024 | 5.314 | −0.314 |
5 | 6.365 | 6.248 | 0.116 | 6.307 | 0.057 | 6.225 | 0.140 |
6 | 5.000 | 4.967 | 0.033 | 5.446 | −0.446 | 5.907 | −0.907 |
7 | 6.367 | 6.230 | 0.137 | 5.931 | 0.436 | 5.911 | 0.456 |
8 | 5.000 | 5.102 | −0.102 | 5.189 | −0.189 | 4.950 | 0.050 |
9 | 5.000 | 5.239 | −0.239 | 5.014 | −0.014 | 5.194 | −0.194 |
10 * | 7.292 | 6.092 | 1.200 | 6.508 | 0.784 | 6.233 | 1.059 |
11 | 6.060 | 6.063 | −0.003 | 5.964 | 0.095 | 6.148 | −0.088 |
12 | 6.461 | 6.453 | 0.008 | 6.401 | 0.060 | 6.052 | 0.409 |
13 | 7.000 | 7.012 | −0.012 | 6.302 | 0.698 | 6.818 | 0.182 |
14 | 7.377 | 7.070 | 0.307 | 7.380 | −0.003 | 6.911 | 0.466 |
15 | 6.870 | 7.040 | −0.170 | 6.452 | 0.418 | 6.517 | 0.353 |
16 | 6.592 | 6.660 | −0.068 | 6.576 | 0.016 | 6.926 | −0.334 |
17 | 6.312 | 6.395 | −0.083 | 6.653 | −0.341 | 6.169 | 0.143 |
18 | 5.000 | 5.062 | −0.062 | 5.449 | −0.449 | 5.846 | −0.846 |
19 | 7.824 | 7.011 | 0.813 | 6.951 | 0.873 | 6.576 | 1.248 |
20 * | 6.959 | 6.528 | 0.431 | 5.916 | 1.043 | 6.666 | 0.293 |
21 | 6.438 | 6.699 | −0.261 | 6.742 | −0.304 | 6.645 | −0.207 |
22 * | 5.952 | 6.461 | −0.509 | 6.993 | −1.041 | 6.700 | −0.748 |
23 * | 5.683 | 5.490 | 0.193 | 5.590 | 0.093 | 6.630 | −0.947 |
24 | 5.428 | 5.327 | 0.101 | 5.574 | −0.146 | 5.521 | −0.093 |
25 | 5.806 | 5.896 | −0.090 | 6.583 | −0.778 | 6.265 | −0.459 |
26 * | 6.556 | 5.894 | 0.662 | 6.111 | 0.445 | 6.740 | −0.184 |
27 | 6.026 | 5.814 | 0.212 | 6.347 | −0.322 | 6.295 | −0.270 |
28 * | 6.023 | 5.744 | 0.279 | 6.477 | −0.454 | 6.749 | −0.726 |
29 | 5.706 | 5.708 | −0.002 | 5.322 | 0.384 | 6.148 | −0.442 |
30 * | 5.692 | 6.086 | −0.394 | 6.111 | −0.419 | 6.328 | −0.636 |
31 | 5.688 | 5.601 | 0.087 | 6.117 | −0.429 | 6.026 | −0.338 |
32 * | 6.334 | 8.044 | −1.711 | 6.289 | 0.045 | 7.253 | −0.920 |
33 | 6.963 | 6.937 | 0.026 | 6.742 | 0.221 | 6.561 | 0.402 |
34 | 7.398 | 7.349 | 0.049 | 7.880 | −0.482 | 7.183 | 0.215 |
35 * | 8.155 | 7.191 | 0.964 | 7.979 | 0.176 | 8.207 | −0.052 |
36 | 5.000 | 5.047 | −0.047 | 4.871 | 0.129 | 5.260 | −0.260 |
37 | 6.824 | 6.803 | 0.021 | 6.603 | 0.221 | 7.167 | −0.343 |
38 | 5.598 | 5.651 | −0.053 | 5.731 | −0.133 | 5.382 | 0.216 |
39 | 6.932 | 7.623 | −0.691 | 6.973 | −0.041 | 6.569 | 0.363 |
40 | 6.016 | 6.033 | −0.017 | 6.427 | −0.411 | 5.770 | 0.246 |
41 * | 6.910 | 6.012 | 0.898 | 6.753 | 0.157 | 7.180 | −0.270 |
42 | 8.097 | 8.147 | −0.050 | 8.069 | 0.028 | 8.308 | −0.211 |
43 | 7.114 | 7.115 | −0.002 | 6.944 | 0.170 | 6.619 | 0.495 |
44 | 8.699 | 8.774 | −0.075 | 8.472 | 0.227 | 8.358 | 0.341 |
45 | 7.456 | 7.337 | 0.119 | 6.944 | 0.512 | 7.701 | −0.245 |
46 * | 5.000 | 5.778 | −0.778 | 5.855 | −0.855 | 4.419 | 0.581 |
47 | 8.398 | 8.364 | 0.034 | 8.644 | −0.246 | 8.514 | −0.116 |
48 * | 8.398 | 8.319 | 0.079 | 8.168 | 0.230 | 7.910 | 0.488 |
49 | 8.222 | 8.041 | 0.181 | 7.951 | 0.271 | 7.944 | 0.278 |
50 * | 7.824 | 7.912 | −0.088 | 7.834 | −0.010 | 7.619 | 0.205 |
51 | 8.155 | 8.241 | −0.086 | 7.889 | 0.266 | 7.766 | 0.389 |
52 | 8.222 | 8.378 | −0.156 | 8.125 | 0.097 | 7.931 | 0.291 |
53 * | 8.523 | 8.002 | 0.521 | 8.126 | 0.397 | 8.239 | 0.284 |
54 | 7.222 | 7.369 | −0.147 | 7.428 | −0.206 | 7.069 | 0.153 |
55 | 7.602 | 7.615 | −0.013 | 8.039 | −0.437 | 7.530 | 0.072 |
56 * | 7.482 | 7.503 | −0.022 | 7.064 | 0.418 | 8.246 | −0.765 |
57 | 6.699 | 6.573 | 0.126 | 6.999 | −0.300 | 6.315 | 0.384 |
58 | 8.523 | 8.441 | 0.082 | 7.866 | 0.657 | 8.501 | 0.022 |
59 | 8.222 | 8.102 | 0.120 | 8.128 | 0.094 | 7.886 | 0.336 |
60 | 6.813 | 6.696 | 0.117 | 6.928 | −0.116 | 7.765 | −0.953 |
61 | 6.697 | 6.888 | −0.191 | 6.960 | −0.263 | 7.513 | −0.816 |
62 * | 7.377 | 7.339 | 0.038 | 7.754 | −0.377 | 7.886 | −0.509 |
63 | 7.222 | 7.253 | −0.031 | 7.863 | −0.641 | 6.816 | 0.406 |
64 * | 6.975 | 6.454 | 0.521 | 5.790 | 1.185 | 7.407 | −0.432 |
65 | 6.827 | 6.790 | 0.037 | 6.234 | 0.593 | 7.473 | −0.646 |
66 * | 7.081 | 6.289 | 0.792 | 6.296 | 0.785 | 7.145 | −0.064 |
67 | 7.357 | 7.293 | 0.063 | 6.725 | 0.632 | 6.899 | 0.458 |
68 | 6.650 | 6.515 | 0.135 | 6.238 | 0.412 | 6.724 | −0.074 |
69 | 6.554 | 6.540 | 0.014 | 7.249 | −0.695 | 7.200 | −0.646 |
70 * | 7.367 | 6.809 | 0.558 | 6.531 | 0.836 | 7.257 | 0.110 |
71 | 7.482 | 7.571 | −0.090 | 7.993 | −0.512 | 7.728 | −0.247 |
72 | 7.284 | 7.357 | −0.073 | 7.314 | −0.030 | 7.624 | −0.340 |
73 | 8.699 | 8.680 | 0.019 | 7.805 | 0.894 | 8.294 | 0.405 |
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Lu, S.; Liu, H.-C.; Chen, Y.-D.; Yuan, H.-L.; Sun, S.-L.; Gao, Y.-P.; Yang, P.; Zhang, L.; Lu, T. Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors. Int. J. Mol. Sci. 2011, 12, 8713-8739. https://doi.org/10.3390/ijms12128713
Lu S, Liu H-C, Chen Y-D, Yuan H-L, Sun S-L, Gao Y-P, Yang P, Zhang L, Lu T. Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors. International Journal of Molecular Sciences. 2011; 12(12):8713-8739. https://doi.org/10.3390/ijms12128713
Chicago/Turabian StyleLu, Shuai, Hai-Chun Liu, Ya-Dong Chen, Hao-Liang Yuan, Shan-Liang Sun, Yi-Ping Gao, Pei Yang, Liang Zhang, and Tao Lu. 2011. "Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors" International Journal of Molecular Sciences 12, no. 12: 8713-8739. https://doi.org/10.3390/ijms12128713