Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors
Abstract
:1. Introduction
2. Computational Methods
2.1. Generation of Multicomplex-Based Pharmacophore Models
2.2. Data Set and Molecular Sketching
2.3. Conformational Model Analysis and Alignment Rule
2.4. CoMFA Study
2.5. Partial Least Square Analysis (PLS) and Model Validation
3. Results and Discussion
3.1. Generation and Validation of Multicomplex-Based Phamacophore
3.2. Alignment of Molecules in the Training and Test Sets
3.3. CoMFA Models
3.4. Graphical Interpretation of the CoMFA Results
4. Conclusion
Acknowledgments
References
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3HF6 | 3HF8 | 3HFB | |
---|---|---|---|
Resolution | 1.80Å | 1.85 Å | 1.92 Å |
Ligand | LXO | MLO | ML4 |
Release date | 2009-11-24 | 2010-04-21 | 2010-04-21 |
Interception residue | |||
Tyr235 | Try235 | Arg257 | |
- | Leu236 | - | |
Arg257 | Arg257 | - | |
Tyr264 | Tyr264 | Tyr264 | |
Thr265 | Pro265 | Pro265 | |
Pro266 | - | - | |
Glu267 | Pro267 | - | |
Pro268 | Pro268 | - | |
His272 | His272 | His272 | |
- | - | Glu306 | |
Phe313 | Phe313 | - | |
Glu317 | Glu317 | Glu317 | |
Ser336 | Ser336 | Ser336 | |
- | - | Ser337 | |
- | Cys364 | Cys364 | |
Pharmacophore model features | |||
Neg 1 | √ | √ | √ |
Donor 1 | √ | √ | √ |
Donor 2 | √ | √ | √ |
Donor 3 | √ | √ | |
Acceptor 1 | √ | √ | |
HP 1 | √ | √ | √ |
HP 2 | √ | √ | √ |
HP 3 | √ | √ | √ |
HP 4 | √ | ||
HP 5 | √ |
PLS Statistics | S | E | S.E. |
---|---|---|---|
rcv2 | 0.467 | 0.359 | 0.570 |
N | 6 | 3 | 6 |
r2 | 0.914 | 0.816 | 0.986 |
SEE | 0.128 | 0.236 | 0.098 |
F-value | 180.43 | 50.10 | 309.77 |
rpred2 | 0.672 | ||
Field Contribution (%) | |||
Steric | 0.829 | ||
Electrostatic | 0.171 |
Compound | Ar | X | R | IC50 | pIC50 | CoMFA pred | Residue |
---|---|---|---|---|---|---|---|
1 | NH | 0.24 | 6.62 | 6.81 | −0.19 | ||
2 * | NH | 0.96 | 6.02 | 5.82 | 0.2 | ||
3 | NH | 0.11 | 6.96 | 6.94 | 0.02 | ||
4 | NH | 6.15 | 5.21 | 5.61 | −0.4 | ||
5 | NH | 0.19 | 6.72 | 6.85 | −0.13 | ||
6 | NH | 0.046 | 7.34 | 7.59 | −0.25 | ||
7 | NH | 0.013 | 7.89 | 7.91 | −0.02 | ||
8 | NH | 0.045 | 7.35 | 7.73 | −0.38 | ||
9 * | NH | 0.031 | 7.51 | 7.55 | −0.04 | ||
10 | NH | 0.069 | 7.16 | 7.14 | 0.02 | ||
11 | NH | 0.044 | 7.36 | 7.47 | −0.11 | ||
12 | NH | 0.04 | 7.40 | 7.66 | −0.26 | ||
13 | NH | 0.026 | 7.59 | 7.40 | 0.19 | ||
14 * | NH | 0.024 | 7.62 | 7.63 | −0.01 | ||
15 | NH | 0.024 | 7.62 | 7.47 | 0.15 | ||
16 | NH | 0.032 | 7.49 | 7.53 | −0.04 | ||
17 | O | 0.38 | 6.42 | 6.89 | −0.47 | ||
18 * | NH | 0.97 | 6.01 | 5.92 | 0.09 | ||
19 | NH | 0.5 | 6.30 | 6.36 | −0.06 | ||
20 | NH | 0.12 | 6.92 | 7.09 | −0.17 | ||
21 * | NH | 0.1 | 7.00 | 6.81 | 0.19 | ||
22 | NH | 0.12 | 6.92 | 6.63 | 0.29 | ||
23 | NH | 0.06 | 7.22 | 7.20 | 0.02 | ||
24 | NH | 0.007 | 8.15 | 8.03 | 0.12 | ||
25 | NH | 0.038 | 7.42 | 7.52 | −0.1 | ||
26 | NH | 0.15 | 6.82 | 6.51 | 0.31 | ||
27 * | NH | 0.014 | 7.85 | 7.81 | 0.04 | ||
28 | NH | 0.16 | 6.80 | 7.02 | −0.22 | ||
29 | NH | 0.044 | 7.36 | 8.13 | −0.77 | ||
30 | NH | 0.055 | 7.26 | 7.41 | −0.15 | ||
31 | NMe | 0.05 | 7.30 | 6.94 | 0.36 | ||
32 | NH | 15.6 | 4.81 | 5.68 | −0.87 |
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Ouyang, L.; He, G.; Huang, W.; Song, X.; Wu, F.; Xiang, M. Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors. Int. J. Mol. Sci. 2012, 13, 5348-5363. https://doi.org/10.3390/ijms13055348
Ouyang L, He G, Huang W, Song X, Wu F, Xiang M. Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors. International Journal of Molecular Sciences. 2012; 13(5):5348-5363. https://doi.org/10.3390/ijms13055348
Chicago/Turabian StyleOuyang, Liang, Gu He, Wei Huang, Xiangrong Song, Fengbo Wu, and Mingli Xiang. 2012. "Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors" International Journal of Molecular Sciences 13, no. 5: 5348-5363. https://doi.org/10.3390/ijms13055348