Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) Studies on α1A-Adrenergic Receptor Antagonists Based on Pharmacophore Molecular Alignment
Abstract
:1. Introduction
2. Materials and Method
2.1. Data Collection
2.2. Structural Sketch and Alignment
2.3. 3D-QSAR Studies
2.4. Predictive Power of the Models
3. Results and Discussion
3.1. Alignment
3.2. CoMFA and CoMSIA Models
3.3. Predictive Power of the Models
3.4. Graphical Interpretation of the Fields
4. Conclusions
Acknowledgments
References
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Series | Compd. No. | R1 | R2 | R3 | X | Ki(nM) | pKi |
---|---|---|---|---|---|---|---|
I | 1 | 4-Cl | −OCH3 | −OCH3 | O | 0.251 | 9.60 |
2 | 2-CH3 | −OCH3 | −OCH3 | O | 1.58 | 8.80 | |
3 | 3-CH3 | −OCH3 | −OCH3 | O | 0.398 | 9.40 | |
4 | 4-CH3 | −OCH3 | −OCH3 | O | 1.99 | 8.70 | |
5 | 3-OCH3 | −OCH3 | −OCH3 | O | 1.99 | 8.70 | |
6 | 4-OCH3 | −OCH3 | −OCH3 | O | 1.99 | 8.70 | |
7 | H | −OCH3 | −OCH3 | S | 3.16 | 8.50 | |
8 | H | −OC2H5 | −OC2H5 | O | 3.16 | 8.50 | |
9 | H | −OC2H5 | −H | O | 2.00 | 8.70 | |
II | 10 | −Cl | − | - | - | 441.29 | 6.36 |
11 | −CH | − | - | - | 467.33 | 6.33 | |
12 | −CN | − | - | - | 170.88 | 6.77 | |
13 | −Br | − | - | - | 301.13 | 6.52 | |
14 | −F | −F | - | - | 108.10 | 6.97 | |
15 | −Cl | −CH3 | - | - | 100.44 | 7.00 | |
16 | −CH3 | −CH3 | - | - | 95.42 | 7.02 | |
17 | −CH3 | −Cl | - | - | 152.20 | 6.82 | |
18 | −CN | −Cl | - | - | 402.56 | 6.39 | |
19 | −Cl | −F | - | - | 86.16 | 7.06 | |
III | 20 | −OCH3 | −OCH3 | - | 0.08 | 10.05 | |
21 | −OCH3 | −OCH3 | - | 0.51 | 9.29 | ||
22 | −OCH3 | −OCH3 | - | 3.23 | 8.49 | ||
IV | 23 | 2-Cl | 5-Cl | - | 95.68 | 7.02 | |
24 | 2-Cl | 5-Cl | - | 264.40 | 6.58 | ||
25 | 2-Cl | 5-Cl | - | 73.57 | 7.13 | ||
26 | 2-OCH3 | - | - | 23.4 | 7.63 | ||
27 | 2-OCH3 | - | - | 43.54 | 7.36 | ||
28 | 2-Cl | 5-Cl | - | 21.77 | 7.66 | ||
29 | 2-OCH3 | - | - | 5.88 | 8.23 | ||
30 | 2-OCH3 | - | - | 7.94 | 8.10 | ||
31 | 2-OCH3 | - | - | 28.84 | 7.54 | ||
V | 32 | - | - | - | - | 629.04 | 6.20 |
Series | Compd. No. | R1 | R2 | R3 | X | Ki(nM) | pKi |
---|---|---|---|---|---|---|---|
I | 33 | 2-Cl | −OCH3 | −OCH3 | O | 1.41 | 8.85 |
II | 34 | −Br | −Br | - | - | 91.25 | 7.04 |
35 | −Cl | −I | - | - | 383.60 | 6.42 | |
III | 36 | −OCH3 | - | - | 27.54 | 7.57 | |
37 | −OCH3 | −OCH3 | - | 2.34 | 8.63 | ||
38 | −OCH3 | −OCH3 | - | 0.40 | 9.40 | ||
39 | −OCH3 | −OCH3 | - | 72.44 | 7.14 | ||
IV | 40 | −Cl | −Cl | - | 2.28 | 8.64 | |
41 | −OCH3 | - | - | 235.52 | 6.63 | ||
42 | −Cl | -Cl | - | 47.86 | 7.32 | ||
43 | −Cl | -Cl | - | 33.93 | 7.47 | ||
V | 44 | 31.62 | 7.50 |
Parameters a | CoMFA | CoMSIA b | ||||
---|---|---|---|---|---|---|
A | B | C | D | E | ||
Optimal PLS component | 4 | 3 | 3 | 3 | 2 | 3 |
q2 | 0.840 | 0.874 | 0.866 | 0.842 | 0.856 | 0.840 |
Scv | 0.476 | 0.407 | 0.419 | 0.456 | 0.427 | 0.459 |
r2 | 0.988 | 0.980 | 0.982 | 0.977 | 0.961 | 0.975 |
SEE | 0.128 | 0.160 | 0.154 | 0.174 | 0.222 | 0.180 |
F | 555.64 | 469.24 | 510.31 | 394.83 | 357.74 | 370.67 |
r2cv | 0.837 | 0.864 | ||||
Fractions | ||||||
Steric | 0.460 | 0.104 | 0.203 | 0.153 | 0.133 | |
Electrostatic | 0.540 | 0.217 | 0.386 | 0.297 | 0.264 | 0.347 |
Hydrophobic | 0.212 | 0.410 | 0.336 | 0.399 | ||
Donnor | 0.183 | 0.360 | ||||
Acceptor | 0.285 | 0.214 | 0.243 | 0.254 | ||
r2pred | 0.694 | 0.646 | 0.581 | 0.576 | 0.663 | 0.671 |
Compd. No. | pKi (exp.) | pKi (pred.) | ΔpKi a | ||
---|---|---|---|---|---|
CoMFA | CoMSIA | CoMFA | CoMSIA | ||
Training set | |||||
1 | 9.60 | 9.620 | 9.561 | −0.0197 | 0.0388 |
2 | 8.80 | 8.743 | 8.896 | 0.0572 | −0.0957 |
3 | 9.40 | 9.410 | 9.273 | −0.0103 | 0.1265 |
4 | 8.70 | 8.593 | 8.680 | 0.1072 | 0.0201 |
5 | 8.70 | 8.659 | 8.687 | 0.0412 | 0.0127 |
6 | 8.70 | 8.649 | 8.777 | 0.0505 | −0.0771 |
7 | 8.50 | 8.510 | 8.611 | −0.0103 | −0.1113 |
8 | 8.50 | 8.440 | 8.676 | 0.0602 | −0.1755 |
9 | 8.70 | 8.689 | 8.843 | 0.0108 | −0.1432 |
10 | 6.36 | 6.505 | 6.694 | −0.1453 | −0.3342 |
11 | 6.33 | 6.385 | 6.474 | −0.0548 | −0.1435 |
12 | 6.77 | 6.652 | 6.716 | 0.1176 | 0.0540 |
13 | 6.52 | 6.559 | 6.605 | −0.0385 | −0.0847 |
14 | 6.97 | 6.923 | 6.901 | 0.0472 | 0.0688 |
15 | 7.00 | 7.113 | 7.035 | −0.1129 | −0.0352 |
16 | 7.02 | 6.880 | 6.690 | 0.1404 | 0.3303 |
17 | 6.82 | 6.793 | 6.656 | 0.0275 | 0.1644 |
18 | 6.39 | 6.475 | 6.641 | −0.0852 | −0.2509 |
19 | 7.06 | 7.011 | 7.024 | 0.0494 | 0.0363 |
20 | 10.05 | 10.126 | 9.768 | −0.0759 | 0.2821 |
21 | 9.29 | 9.294 | 9.181 | −0.0042 | 0.1095 |
22 | 8.49 | 8.601 | 8.751 | −0.1107 | −0.2609 |
23 | 7.02 | 6.871 | 6.661 | 0.1492 | 0.3588 |
24 | 6.58 | 6.590 | 6.691 | −0.0096 | −0.1111 |
25 | 7.13 | 7.177 | 7.202 | −0.0472 | −0.072 |
26 | 7.63 | 7.653 | 7.404 | −0.0229 | 0.2259 |
27 | 7.36 | 7.365 | 7.290 | −0.0055 | 0.0698 |
28 | 7.66 | 7.697 | 7.423 | −0.0371 | 0.2370 |
29 | 8.23 | 8.275 | 8.179 | −0.0451 | 0.0512 |
30 | 8.10 | 8.070 | 8.265 | 0.0305 | −0.1652 |
31 | 7.54 | 7.576 | 7.631 | −0.0364 | −0.0906 |
32 | 6.20 | 6.217 | 6.235 | −0.0173 | −0.0351 |
Test set | |||||
33 | 8.85 | 8.587 | 9.010 | 0.2629 | −0.1603 |
34 | 7.04 | 6.766 | 6.613 | 0.2737 | 0.4265 |
35 | 6.42 | 6.669 | 6.653 | −0.2490 | −0.2334 |
36 | 7.57 | 8.514 | 8.370 | −0.9437 | −0.800 |
37 | 8.63 | 8.174 | 8.723 | 0.4563 | −0.0931 |
38 | 9.40 | 9.804 | 9.128 | −0.4037 | 0.2719 |
39 | 7.14 | 7.916 | 7.652 | −0.7758 | −0.5117 |
40 | 8.64 | 7.996 | 7.506 | 0.6440 | 1.1341 |
41 | 6.63 | 6.584 | 6.848 | 0.0461 | −0.2182 |
42 | 7.32 | 7.794 | 6.801 | −0.4744 | 0.5191 |
43 | 7.47 | 6.974 | 7.079 | 0.4955 | 0.3908 |
44 | 7.50 | 7.341 | 7.852 | 0.1589 | −0.3518 |
r2predb | 0.694 | 0.671 |
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Zhao, X.; Chen, M.; Huang, B.; Ji, H.; Yuan, M. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) Studies on α1A-Adrenergic Receptor Antagonists Based on Pharmacophore Molecular Alignment. Int. J. Mol. Sci. 2011, 12, 7022-7037. https://doi.org/10.3390/ijms12107022
Zhao X, Chen M, Huang B, Ji H, Yuan M. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) Studies on α1A-Adrenergic Receptor Antagonists Based on Pharmacophore Molecular Alignment. International Journal of Molecular Sciences. 2011; 12(10):7022-7037. https://doi.org/10.3390/ijms12107022
Chicago/Turabian StyleZhao, Xin, Minsheng Chen, Biyun Huang, Hong Ji, and Mu Yuan. 2011. "Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) Studies on α1A-Adrenergic Receptor Antagonists Based on Pharmacophore Molecular Alignment" International Journal of Molecular Sciences 12, no. 10: 7022-7037. https://doi.org/10.3390/ijms12107022