3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis
1. Introduction
2. Result and Disscussion
2.1. Binding Site and Docking Results
No. | R1 | R2 | R3 | Obs.pI50 a | Pred.pI50 b | Dev. c | DS d |
---|---|---|---|---|---|---|---|
1 | 2,4-Cl | H | 3.98 | 4.013 | −0.033 | −7.1 | |
2 f | 2,4-Cl | Br | 5.28 | 4.710 | 0.570 | −7.3 | |
3 f | 2,4-F | H | 3.02 | 4.164 | −1.144 | −7.2 | |
4 | 2,4-F | Br | 3.74 | 3.749 | −0.009 | −7.6 | |
5 | 4-F | Br | 3.41 | 3.381 | 0.029 | −7.6 | |
6 f | 4-Cl | Br | 3.73 | 3.663 | 0.067 | −7.5 | |
7 | 4-NO2 | Br | 3.75 | 3.772 | −0.022 | −7.1 | |
8 | H | Br | 3.99 | 3.950 | 0.040 | −7.2 | |
9 f | 2,4-CH3 | Br | 3.42 | 3.980 | −0.560 | −7.7 | |
10 e | 2,4-Cl | O | 5.82 | 5.886 | −0.066 | −7.3 | |
11 e | 2,4-Cl | O | 4.87 | 4.776 | 0.094 | −7.3 | |
12 | 4-F | O | 4.24 | 4.266 | −0.026 | −7.6 | |
13 | 4-Cl | O | 4.27 | 4.362 | −0.092 | −7.1 | |
14 | 4-NO2 | O | 4.29 | 4.281 | 0.009 | −7.3 | |
15 e | 4-Phenyl | O | 5.83 | 5.784 | 0.046 | −7.2 | |
16 f | 2,4-Cl | S | 4.34 | 5.380 | −1.040 | −6.9 | |
17 e | H | O | 4.52 | 4.447 | 0.073 | −7.4 | |
18 | 2,4-CH3 | O | 4.39 | 4.429 | −0.039 | −7.2 | |
19 e | 2,4-F | 4-Cl | 4.42 | 4.403 | 0.017 | −7.0 | |
20 | 2,4-F | 4-F | 4.10 | 4.121 | −0.021 | −8.2 | |
21 f,g | 6.44 | 6.020 | 0.420 | −7.6 |
2.2. Pharmacophore and Alignments
Model | FEATS | SE | SO | PhS |
---|---|---|---|---|
M_01 | 9 | 1.93 | 642.6 | 199.1 |
M_02 | 8 | 1.65 | 641.6 | 191.5 |
M_03 | 8 | 3.62 | 671.7 | 191.5 |
M_04 | 9 | 4.39 | 684 | 191.5 |
M_05 | 8 | 4.19 | 710.3 | 193.1 |
M_06 | 8 | 4.62 | 671 | 192.3 |
M_09 | 8 | 1.37 | 310.4 | 124.1 |
M_10 | 8 | 1.61 | 327.4 | 120.7 |
M_13 | 7 | 1.14 | 280.9 | 119.2 |
M_17 | 7 | 0.64 | 160.7 | 102.7 |
Min a | 0.64 | 160.7 | 102.7 | |
Max b | 4.62 | 710.3 | 199.1 |
2.3. 3D-QSAR
Parameters | COMFA | COMSIA | |||||
---|---|---|---|---|---|---|---|
IA | IB | IC | ID | IE | IF | ||
Component | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
q2a | 0.521 | 0.694 | 0.736 | 0.681 | 0.749 | 0.714 | 0.671 |
Scvb | 0.629 | 0.503 | 0.467 | 0.514 | 0.455 | 0.487 | 0.522 |
rcv c | 0.488 | 0.655 | 0.702 | 0.687 | 0.722 | 0.707 | 0.758 |
rncv2 d | 0.999 | 0.992 | 0.992 | 0.995 | 0.995 | 0.992 | 0.994 |
F e | 1049.253 | 174.433 | 163.561 | 243.308 | 291.917 | 174.561 | 214.532 |
SEE f | 0.032 | 0.079 | 0.082 | 0.067 | 0.061 | 0.079 | 0.071 |
Fraction | |||||||
Steric | 0.466 | 0.084 | 0.095 | 0.087 | 0.119 | 0.096 | |
Electrostatic | 0.534 | 0.425 | 0.503 | 0.553 | 0.708 | 0.484 | 0.488 |
Hydrophobic | 0.130 | 0.147 | 0.152 | 0.173 | 0.143 | ||
Donor | 0.199 | 0.255 | 0.193 | 0.233 | |||
Acceptor | 0.157 | 0.209 | 0.180 | 0.192 | |||
g | 0.446 | 0.516 | 0.435 | 0.611 | 0.554 | 0.548 | 0.477 |
2.4. Mtb Cell Wall Permeability Prediction
Parameters | IIA | IIB | IIC | IID | IIE | IIF | IIG |
---|---|---|---|---|---|---|---|
n a | 77 | 77 | 77 | 77 | 77 | 77 | 77 |
q2 b | 0.475 | 0.468 | 0.436 | 0.594 | 0.583 | 0.597 | 0.598 |
r2c | 0.497 | 0.497 | 0.463 | 0.624 | 0.609 | 0.645 | 0.648 |
r | 0.704 | 0.704 | 0.680 | 0.789 | 0.780 | 0.803 | 0.804 |
F d | 73.98 | 74.03 | 64.68 | 61.29 | 57.51 | 67.20 | 67.98 |
SEE e | 0.537 | 0.537 | 0.554 | 0.467 | 0.477 | 0.454 | 0.450 |
logD f | 0.313 | 0.212 | 0.192 | 0.225 | 0.200 | ||
PSA g | −0.006 | −0.004 | −0.004 | ||||
HCPSA h | −0.011 | −0.007 | −0.007 | ||||
rgyr i | −0.082 | −0.130 | |||||
frtobj | 0.431 | 0.362 | |||||
c k | −5.261 | −4.313 | −4.278 | −4.685 | −4.707 | −4.497 | −4.313 |
No. | logPeff a | rgyr b | frtob c | logD d | PSA e |
---|---|---|---|---|---|
1 | −4.6116343 | 4.0313 | 0.2000 | 2.46 | 149.838 |
2 | −4.5404066 | 3.9282 | 0.1904 | 2.67 | 147.268 |
3 | −4.8524414 | 3.8254 | 0.2000 | 1.39 | 152.410 |
4 | −4.7692208 | 3.6884 | 0.1904 | 1.59 | 145.796 |
5 | −4.7926759 | 3.7089 | 0.2000 | 1.50 | 147.788 |
6 | −4.7023681 | 3.9511 | 0.2000 | 2.05 | 150.179 |
7 | −5.0909159 | 4.0777 | 0.2272 | 1.24 | 239.008 |
8 | −4.7872804 | 3.4399 | 0.2105 | 1.31 | 150.507 |
9 | −4.6492473 | 3.6979 | 0.1904 | 2.15 | 156.862 |
10 | −4.5570507 | 4.0205 | 0.2272 | 2.41 | 127.883 |
11 | −4.8030476 | 3.8244 | 0.2272 | 1.33 | 130.829 |
12 | −4.8236766 | 3.8606 | 0.2380 | 1.24 | 130.382 |
13 | −4.7282331 | 4.0861 | 0.2380 | 1.79 | 131.800 |
14 | −5.1202633 | 4.2235 | 0.2608 | 0.98 | 219.603 |
15 | −4.5974279 | 4.8307 | 0.2222 | 2.89 | 130.405 |
16 | −4.4095507 | 4.0205 | 0.2272 | 3.09 | 141.513 |
17 | −4.8078457 | 3.5847 | 0.2500 | 1.05 | 129.134 |
18 | −4.6659152 | 3.8600 | 0.2272 | 1.89 | 130.823 |
19 | −4.0633268 | 4.0268 | 0.2580 | 4.05 | 103.310 |
20 | −4.1658948 | 4.2228 | 0.2580 | 3.79 | 102.466 |
21 | −4.5433115 | 4.2727 | 0.2222 | 2.86 | 152.777 |
3. Experimental
3.1. Data Set
3.2. Predicted Binding Sites and Docking Simulation of DDN
3.3. Pharmacophore Model and Molecular Alignment
3.4. 3D-QSAR Models
3.5. MTB Cell Wall Permeability Prediction
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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Lee, S.-H.; Choi, M.; Kim, P.; Myung, P.K. 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis. Molecules 2013, 18, 13870-13885. https://doi.org/10.3390/molecules181113870
Lee S-H, Choi M, Kim P, Myung PK. 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis. Molecules. 2013; 18(11):13870-13885. https://doi.org/10.3390/molecules181113870
Chicago/Turabian StyleLee, Sang-Ho, Minsung Choi, Pilho Kim, and Pyung Keun Myung. 2013. "3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis" Molecules 18, no. 11: 13870-13885. https://doi.org/10.3390/molecules181113870