QSAR Study of p56lck Protein Tyrosine Kinase Inhibitory Activity of Flavonoid Derivatives Using MLR and GA-PLS
Abstract
:1. Introduction
2. Results and Discussion
2.1. MLR analysis
2.2. Free-Wilson analysis
2.3. GA-PLS analysis
3. Methodology
3.1. Software
3.2. Activity data & descriptor generation
3.3. Data screening & model building
3.4. Variable importance in the projection (VIP)
3.5. Substituent electronic descriptors (SED)
4. Conclusions
Acknowledgments
References
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Compound | R | Experimental pIC50a | Predicted pIC50 | REP b |
---|---|---|---|---|
1 | 5,7-OH,4′-NH2 | 5.13 | 4.7707 | −0.0753 |
2 | 3,5,7,3′,4′-OH | 4.88 | 4.9431 | 0.0128 |
3 | 3,7,3′,4′-OH | 4.86 | 4.7707 | −0.0187 |
4 | 5,7,4′-OH | 4.83 | 4.4356 | −0.0889 |
5 | 5,4′-OH | 4.80 | 4.2603 | −0.1267 |
6 | 6,3′-OH | 4.80 | 4.4242 | −0.0849 |
7 | 6-OH,5,7,4′-NH2 | 4.74 | 4.1061 | −0.1544 |
8 | 5,7-OH | 4.71 | 4.0895 | −0.1518 |
9 | 4′-OH,3′,5′-OCH3 | 4.57 | 4.2687 | −0.0706 |
10 | 5,7,3′,4′-OH | 4.46 | 4.4172 | −0.0097 |
11 | 7,3′-OH | 4.41 | 4.4358 | 0.0058 |
12 | 6-OH,5,7,3′-NH2 | 4.34 | 4.3681 | 0.0064 |
13 | 6-OMe,8,3′-NH2 | 4.25 | 4.1649 | −0.0204 |
14 | 6-OH,3′,4′,5′-OCH3 | 4.22 | 4.3591 | 0.0319 |
15 | 3,5,7,4′-OH,3′,5′-OCH3 | 4.16 | 4.1649 | 0.0012 |
16 | 3,5,7,3′,5′-OH | 4.00 | 3.9947 | −0.0013 |
17 | 6,4′-NH2 | 3.99 | 3.9613 | −0.0072 |
18 | 6,8,4′-NH2 | 3.97 | 3.9764 | 0.0016 |
19 | 6-OH,8,4′-NH2 | 3.93 | 3.9446 | 0.0037 |
20 | 6,4′-OH | 3.93 | 3.9247 | −0.0013 |
21 | 7,8,4′-OH,3′,5′-OCH3 | 3.92 | 3.8990 | −0.0054 |
22 | 8,4′-NH2 | 3.91 | 3.8994 | −0.0027 |
23 | 6,4′-OH,3′,5′-OCH3 | 3.89 | 3.9133 | 0.0060 |
24 | 7-OH,4′-NH2 | 3.86 | 3.8815 | 0.0056 |
25 | 7-OH,6,4′-NH2 | 3.85 | 3.8296 | −0.0053 |
26 | 7,4′-OH | 3.78 | 3.8621 | 0.0213 |
27 | 7,8,3′OH | 3.75 | 3.6903 | −0.0162 |
28 | 6,3′-NH2 | 3.70 | 4.0228 | 0.0803 |
29 | 4′-NH2 | 3.68 | 4.1850 | 0.1207 |
30 | 5-OH,6,4′-NH2 | 3.65 | 3.9325 | 0.0718 |
31 | 3,5,7-OH | 3.53 | 3.9794 | 0.1129 |
32 | 5,4′-OH,7-OCH3 | 3.55 | 3.7315 | 0.0487 |
33 | 5,3′-OH | 3.50 | 4.1209 | 0.1507 |
34 | 7,8-OH | 3.50 | 3.4873 | −0.0036 |
35 | 5-OH,8,4′-NH2 | 3.49 | 3.6705 | 0.0492 |
36 | 7-OH,8,4′-NH2 | 3.48 | 3.6694 | 0.0516 |
37 | 7-OH | 3.47 | 3.8567 | 0.1003 |
38 | 6-OCH3,8,4′-NH2 | 3.43 | 3.6709 | 0.0683 |
39 | 7,8-OH,3′,4′,5′-OCH3 | 3.40 | 4.0058 | 0.1512 |
40 | 3-COOCH3,4′-OH | 3.36 | 3.7081 | 0.0939 |
41 | 4′-OH | 3.30 | 3.7081 | 0.1101 |
42 | 7-OH,6,3′-NH2 | 3.30 | 3.3419 | 0.0125 |
43 | 7-OH,6,8,4′-NH2 | 3.12 | 3.3419 | 0.0664 |
44 | 3-COOCH3,4′-NH2 | 3.09 | 3.3419 | 0.0754 |
45 | 3-COOH,7-OCH3,4′-OH | 2.99 | 3.3262 | 0.1011 |
46 | 7,4′-OH,3′,5′-OCH3 | 2.90 | 3.3262 | 0.1281 |
47 | 7-OH,6,8,4′-NO2 | 2.81 | 3.0674 | 0.0839 |
48 | 3-COOH,4′-OH | 2.80 | 3.0674 | 0.0872 |
49 | 5-OCH3,8,4′-NH2 | 2.79 | 3.0674 | 0.0904 |
50 | 7-OH,8,4′-NO2 | 2.73 | 3.3262 | 0.1793 |
Descriptor type | Molecular Description |
---|---|
Constitutional | Molecular weight, no. of atoms, no. of non-H atoms, no. of bonds, no. of heteroatoms, no. of multiple bonds (nBM), no. of aromatic bonds, no. of functional groups (hydroxyl, amine, aldehyde, carbonyl, nitro, nitroso, etc.), no. of rings, no. of circuits, no of H-bond donors, no of H-bond acceptors, no. of Nitrogen atoms (nN), chemical composition, sum of Kier-Hall electrotopological states (Ss), mean atomic polarizability (Mp), number of rotable bonds (RBN), mean atomic Sanderson electronegativity (Me), etc.
|
Topological | Molecular size index, molecular connectivity indices (X1A, X4A, X2v, X1Av, X2Av, X3Av, X4Av), information content index (IC), Kier Shape indices, total walk count, path/walk-Randic shape indices (PW3, PW4, Zagreb indices, Schultz indices, Balaban J index (such as MSD) Wiener indices, topological charge indices, Sum of topological distances between F..F (T(F..F)), Ratio of multiple path count to path counts (PCR), Mean information content vertex degree magnitude (IVDM), Eigenvalue sum of Z weighted distance matrix (SEigZ), reciprocal hyper-detour index (Rww), Eigenvalue coefficient sum from adjacency matrix (VEA1), radial centric information index, 2D petijean shape index (PJI2), etc.
|
Geometrical | 3D petijean shape index (PJI3), Gravitational index, Balaban index, Wiener index, etc.
|
Quantum | Highest occupied Molecular Orbital Energy (HOMO) , Lowest Unoccupied Molecular Orbital Energy (LUMO), Most positive charge (MPC), Least negative charge (LNC), Sum of squares of charges (SSC), Sum of square of positive charges (SSPC), Sum of square of negative charges (SSNC), Sum of positive charges (SUMPC), Sum of negative charges (SUMNC), Sum of absolute of charges (SAC), Total dipole moment (DMt), Molecular dipole moment at X-direction (DMX), Molecular dipole moment at Y-direction (DMY), Molecular dipole moment at Z-direction (DMZ), Electronegativity (χ= −0.5 (HOMO-LUMO)), Electrophilicity (ω= χ2/2 η) ,Hardness (η = 0.5 (HOMO+LUMO)), Softness (S=1/η).
|
Functional group | Number of total tertiary carbons (nCt), Number of H-bond acceptor atoms (nHAcc), number of total hydroxyl groups (nOH), number of unsubstituted aromatic C(nCaH), number of ethers (aromatic) (nRORPh), etc.
|
Chemical | LogP (Octanol-water partition coefficient), Hydration Energy (HE), Polarizability (Pol), Molar refractivity (MR), Molecular volume (V), Molecular surface area (SA).
|
Substituent electronic descriptors | RMSQ (Root mean square error of charges), SPQ ( Sum of positive charges), SNQ ( Sum of negative charges), RMSDM (Root mean square of dipole moments at any Cartesian coordinate direction), TDM (Total dipole moment), FRMS (Root mean square force that any atom in constituent molecule see right before the optimization), FMAX (Maximum force on molecule), HOMO (Highest occupied molecular orbital), LUMO (Lowest unoccupied molecular orbital), HD (Hardness), SOF (Softness), EPH (Electrophilicity), EN (Electronegativity). |
No. | Descriptor source | MLR Equations | N | R2 | SE | RMSCV | Q2 | F |
---|---|---|---|---|---|---|---|---|
E1 | Chemical | pIC50 = 4.893 (± 0.735) − 0.056 (± 0.017) HE −0.007 (± 0.003) Mass | 50 | 0.40 | 0.55 | 0.58 | 0.32 | 13.82 |
E2 | Quantum | pIC50 = 6.362 (± 0.565) − 6.805 (± 1.505) MPC | 50 | 0.43 | 0.53 | 0.54 | 0.38 | 17.44 |
E3 | Constitutional | pIC50 = 3.139 (± 1.250) − 0.438 (± 0.100) nBM − 0.506 (± 0.205) AMW − 0.584 (± 0.266) nAB | 50 | 0.49 | 0.49 | 0.51 | 0.42 | 19.65 |
E4 | Topological | pIC50 = 17.242 (± 0.605) − 3.374 (± 0.545) IVDM − 53.95 (± 12.355) X1Av + 2.349 (± 0.696) ICR +24.874 (±9.569) PW4 + 73.575 (±33.719) X4A | 50 | 0.72 | 0.38 | 0.48 | 0.58 | 30.13 |
E5 | Geometrical | pIC50 = −15.093 (± 3.339) + 19.450 (± 3.406) SPH − 0.010 (± 0.002) G(N...O) | 50 | 0.60 | 0.43 | 0.47 | 0.49 | 17.23 |
E6 | Functional group | pIC50 = 3.672 (± 0.123) − 0.414 (± 0.130) nNO2 −1.098 (± 0.369) nOHt + 0.160 (± 0.058) nOH | 50 | 0.53 | 0.45 | 0.50 | 0.45 | 12.67 |
E7 | Hansch | pIC50 = 4.219 (± 0.289) − 0.615 (± 0.202) π5 + 1.462 (± 0.555) ℑR′3 − 1.379 (± 0.490) ℑR8 −0.249 (± 0.111) L3 | 50 | 0.53 | 0.45 | 0.50 | 0.45 | 12.67 |
E8 | SED | pIC50 = −0.708 (± 1.228) − 9.570 (± 2.500) HOMOA3 + 1.092 (±0.308) SNQ8 | 50 | 0.82 | 0.32 | 0.30 | 0.61 | 51.43 |
E9 | Molecular descriptor | pIC50 = −19.763 (± 4.304) − 4.785 (± 1.275) MPC + 25.113 (± 4.142) SPH + 0.849 (± 0.264) SNQ8 − 0.357 (± 0.136) L3 | 50 | 0.83 | 0.31 | 0.28 | 0.62 | 52.43 |
HE | Mass | MPC | nBM | AMW | nAB | ASP | G(N...O) | X1AV | ICR | PW4 | X4A | IVDM | nNO2 | nOHt | nOH | ℑR′3 | L3 | ℑR8 | π5 | pIC50 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HE | 1 | −0.234 | 0.192 | 0.124 | −0.327 | 0.236 | −0.006 | 0.00 | 0.651 | 0.075 | −0.012 | 0.316 | 0.065 | 0.069 | 0.047 | −0.745 | −0.394 | 0.067 | −0.005 | 0.485 | −0.347 |
Mass | 1 | 0.531 | 0.580 | 0.512 | 0.136 | −0.269 | 0.328 | −0.655 | 0.416 | 0.541 | −0.631 | 0.816 | 0.554 | 0.099 | 0.211 | 0.326 | 0.196 | 0.487 | 0.040 | −0.268 | |
MPC | 1 | 0.953 | 0.715 | 0.366 | −0.233 | 0.623 | −0.539 | 0.304 | 0.050 | −0.329 | 0.904 | 0.876 | 0.259 | −0.227 | −0.286 | 0.289 | 0.595 | 0.156 | −0.547 | ||
nBM | 1 | 0.778 | 0.165 | −0.094 | 0.725 | −0.624 | 0.390 | 0.016 | −0.325 | 0.937 | 0.972 | 0.114 | −0.196 | −0.211 | 0.125 | 0.687 | 0.193 | −0.498 | |||
AMW | 1 | 0.050 | −0.200 | 0.356 | 0.897 | 0.037 | 0.116 | −0.206 | 0.718 | 0.775 | 0.116 | 0.434 | 0.136 | 0.125 | 0.620 | 0.065 | −0.191 | ||||
nAB | 1 | −0.684 | −0.127 | 0.069 | −0.192 | 0.257 | −0.397 | 0.235 | −0.073 | 0.692 | −0.086 | −0.198 | 0.930 | −0.108 | 0.185 | −0.364 | |||||
ASP | 1 | 0.294 | 0.155 | 0.538 | 0.532 | 0.388 | −0.221 | 0.069 | 0.369 | −0.273 | −0.201 | −0.768 | −0.039 | −0.098 | 0.269 | ||||||
G(N...O) | 1 | −0.379 | 0.578 | 0.299 | 0.348 | 0.618 | 0.763 | −0.138 | −0.478 | −0.437 | −0.182 | 0.508 | 0.034 | −0.329 | |||||||
X1AV | 1 | −0.130 | −0.171 | 0.413 | −0.651 | −0.647 | −0.052 | −0.572 | −0.270 | −0.056 | −0.542 | 0.229 | 0.058 | ||||||||
ICR | 1 | −0.212 | −0.277 | 0.442 | 0.441 | −0.104 | −0.410 | −0.161 | −0.278 | 0.153 | 0.168 | −0.080 | |||||||||
PW4 | 1 | −0.157 | 0.261 | −0.045 | 0.158 | 0.336 | 0.413 | 0.356 | 0.029 | −0.249 | 0.002 | ||||||||||
X4A | 1 | −0.489 | −0.233 | −0.252 | −0.046 | −0.025 | −0.466 | −0.261 | −0.157 | 0.347 | |||||||||||
IVDM | 1 | 0.891 | 0.155 | −0.100 | −0.030 | 0.218 | 0.663 | 0.192 | −0.494 | ||||||||||||
nNO2 | 1 | −0.050 | −0.177 | −0.166 | −0.097 | 0.720 | 0.151 | −0.416 | |||||||||||||
nOHt | 1 | 0.061 | −0.137 | 0.513 | −0.075 | 0.128 | −0.306 | ||||||||||||||
nOH | 1 | 0.621 | 0.104 | −0.004 | −0.375 | 0.370 | |||||||||||||||
ℑR′3 | 1 | −0.070 | 0.008 | −0.014 | 0.315 | ||||||||||||||||
L3 | 1 | −0.143 | 0.085 | −0.259 | |||||||||||||||||
ℑR8 | 1 | 0.224 | −0.367 | ||||||||||||||||||
π5 | 1 | −0.451 | |||||||||||||||||||
pIC50 | 1 |
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Fassihi, A.; Sabet, R. QSAR Study of p56lck Protein Tyrosine Kinase Inhibitory Activity of Flavonoid Derivatives Using MLR and GA-PLS. Int. J. Mol. Sci. 2008, 9, 1876-1892. https://doi.org/10.3390/ijms9091876
Fassihi A, Sabet R. QSAR Study of p56lck Protein Tyrosine Kinase Inhibitory Activity of Flavonoid Derivatives Using MLR and GA-PLS. International Journal of Molecular Sciences. 2008; 9(9):1876-1892. https://doi.org/10.3390/ijms9091876
Chicago/Turabian StyleFassihi, Afshin, and Razieh Sabet. 2008. "QSAR Study of p56lck Protein Tyrosine Kinase Inhibitory Activity of Flavonoid Derivatives Using MLR and GA-PLS" International Journal of Molecular Sciences 9, no. 9: 1876-1892. https://doi.org/10.3390/ijms9091876