Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors
Abstract
:1. Introduction
2. Results
2.1. Molecular Docking
2.2. Molecular Dynamics Simulation
2.3. Evaluation of Binding Energy
2.4. D-QSAR
2.5. Analysis of Contour Map
2.6. Designed Compounds
3. Discussion
4. Methodology
4.1. Data Preparation
4.2. Molecular Docking
4.3. Molecular Dynamics Simulation
4.4. Evaluation of Binding Energy
4.5. 3D-QSAR
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
S | Steric |
E | Electrostatic |
H | Hydrophobic |
ADMET | Absorption, distribution, metabolism, excretion and toxicity |
BE | Binding energy |
BS SD | Bootstrap standard deviation |
CADD | Computer-aided drug discovery |
c-KIT | Stem cell factor receptor |
CoMFA | Comparative molecular field analysis |
CoMSIA | Comparative molecular similarity indices analysis |
FDA | Food and Drug Administration |
FGFR | Fibroblast growth factor receptor |
FLT3 | Fms like tyrosine kinase 3 |
GISTs | Gastrointestinal stromal tumors |
ICC | Interstitial cells of Cajal |
MD | Molecular dynamics |
MM/PBSA | Molecular mechanics energies combined with the Poisson–Boltzmann and surface area continuum solvation |
ONC | Optimal number of components |
PDB | Protein data bank |
PDGFRa | Platelet derived growth factor receptor alpha |
RAF1 | Rapidly accelerated fibrosarcoma 1 |
RET | Rearranged during transfection |
RMSD | Root mean square deviation |
SASA | Solvent accessible surface area |
SEE | Standard error of estimation |
VEGFR | Vascular endothelial growth factor receptor |
3D-QSAR | Three-dimensional quantitative structure–activity relationship |
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Structure A | ||||
---|---|---|---|---|
Compounds | Structures | R1 | c-KIT (pIC50) | PDGFRα (pIC50) |
1 | 8.62 | 7.06 | ||
2 | 8.43 | 7.49 | ||
3 | >4.3 | >4.3 | ||
4 | 5.2 | >4.3 | ||
5 | A | 8.41 | 7.66 | |
6 | A | 4.96 | 6.52 | |
7 | A | 5.74 | 7.19 | |
8 | A | 5.32 | 6.58 | |
9 | A | 5.62 | 6.74 | |
10 | A | 6.70 | 4.67 | |
11 | A | 7.72 | 6.67 | |
12 | A | 5.71 | 5.75 | |
13 | A | 8.14 | 6.90 | |
14 | A | 8.62 | 8.14 | |
15 | A | 5.65 | 5.96 | |
16 | A | 5.34 | 6.03 | |
17 | A | 6.40 | 4.72 | |
18 | A | 5.19 | 5.39 | |
19 | A | 7.92 | 6.87 | |
20 | A | 7.92 | 6.75 | |
21 | A | 8.59 | 7.08 | |
22 | A | 8.03 | 6.51 | |
23 | A | 4.66 | 5.34 | |
24 | A | 4.4 | >4.3 | |
25 | A | 4.7 | >4.3 | |
26 | A | 4.69 | 4.36 | |
27 | A | 8.46 | 6.79 | |
28 | A | 8.85 | 7.57 | |
29 | A | 6.49 | 5.95 | |
30 | A | 5.85 | 5.83 | |
31 | A | 6.26 | 5.95 | |
32 | A | 6.50 | 6.14 | |
33 | A | 6.84 | 6.24 | |
34 | A | >4.3 | >4.3 | |
35 | A | 7.29 | 6.41 | |
36 | A | 7.59 | 6.80 | |
37 | A | 7.11 | 6.33 | |
38 | A | >4.3 | >4.3 | |
39 | A | 8.43 | 7.09 | |
40 | A | 8.77 | 7.62 | |
41 | A | 8.21 | 6.87 | |
42 | A | 8.06 | 7.08 | |
43 | A | 6.92 | 6.39 | |
44 | A | 7.70 | 6.40 | |
45 | A | 7.85 | 6.50 | |
46 | A | 8.72 | 7.66 | |
47 | A | 7.70 | 6.91 | |
48 | A | 8.44 | 7.01 |
Complexes | Van der Waals (kJ/Mol) | Electrostatics (kJ/Mol) | Polar Solvation (kJ/Mol) | SASA (kJ/Mol) | Total Binding Energy (kJ/Mol) |
---|---|---|---|---|---|
Imatinib–c-KIT | −260 | −74 | 257 | −28 | −105 |
Imatinib–PDGFRα | −244 | −58 | 225 | −27 | −104 |
Compound 14–c-KIT | −257 | −57 | 219 | −25 | −120 |
Compound 14–PDGFRα | −251 | −55 | 213 | −25 | −118 |
Compound 31–c-KIT | −183 | −48 | 185 | −19 | −65 |
Compound 31–PDGFRα | −180 | −50 | 163 | −18 | −85 |
Imatinib–c-KIT/I670 | −227 | −48 | 228 | −26 | −73 |
Imatinib–PDGFRα/I674 | −248 | −18 | 227 | −28 | −67 |
Compound 14–c-KIT/I670 | −250 | −61 | 205 | −25 | −131 |
Compound 14–PDGFRα/I674 | −265 | −39 | 203 | −25 | −126 |
c-KIT Residues | Compound 14–c-KIT (kJ/mol) | Imatinib–c-KIT (kJ/mol) | PDGFRα Residues | Compound 14–PDGFRα (kJ/mol) | Imatinib–PDGFRα (kJ/mol) |
---|---|---|---|---|---|
Asp572 | −0.9 | −0.7 | Glu587 | −0.66 | −0.42 |
Leu595 | −2.6 | −3.4 | Leu599 | −2.48 | −2.87 |
Val603 | −5.4 | −3.2 | Gly600 | −0.91 | −0.82 |
Ala621 | −2.7 | −3.1 | Val607 | −5.23 | −5.10 |
Val620 | −0.7 | −0.8 | Val608 | −1.10 | −0.69 |
Val622 | −1.0 | −1.7 | Glu609 | −1.31 | −2.33 |
Glu635 | −0.8 | −0.7 | Val624 | −0.76 | −1.10 |
Val643 | −3.1 | −3.6 | Ala625 | −2.20 | −1.87 |
Leu644 | −6.7 | −6.6 | Val626 | −1.15 | −1.84 |
Leu647 | −2.1 | −0.5 | Glu637 | −0.83 | −0.96 |
Ile653 | −3.0 | −0.9 | Ile647 | −4.19 | −4.35 |
Val654 | −5.2 | −7.6 | Met648 | −8.93 | −7.98 |
Tyr672 | −3.9 | −5.6 | Leu651 | −2.11 | −0.96 |
Cys673 | −2.1 | −2.5 | Ile657 | −2.52 | −0.76 |
Gly676 | −0.8 | −0.4 | Val658 | −5.46 | −5.28 |
Leu783 | −2.9 | −0.6 | Ile672 | −0.83 | −2.95 |
Cys788 | −1.3 | −1.8 | Tyr676 | −3.39 | −4.99 |
His790 | −3.6 | −1.9 | Cys677 | −2.48 | −1.82 |
Asp792 | −1.0 | −0.2 | Gly680 | −0.92 | −0.76 |
Leu799 | −4.9 | −4.3 | Leu809 | −2.58 | −1.14 |
Lys807 | −1.1 | 2.2 | Cys814 | −2.27 | −1.81 |
Ile808 | −1.0 | 0.4 | Leu825 | −5.59 | −5.59 |
Cys809 | −6.4 | −6.2 | Ile834 | −1.21 | −0.40 |
Asp810 | −2.1 | 9.3 | Cys835 | −6.27 | −5.11 |
Phe811 | −6.8 | −4.0 | Asp836 | −5.11 | 1.89 |
Asp851 | −1.5 | −0.5 | Phe837 | −4.87 | −7.16 |
Parameters | CoMFA (c-KIT) | CoMSIA (c-KIT) | CoMFA (PDGFRα) | CoMSIA (PDGFRα) |
---|---|---|---|---|
q2 | 0.63 | 0.6 | 0.61 | 0.62 |
ONC | 6 | 5 | 6 | 3 |
r2 | 0.98 | 0.9 | 0.98 | 0.81 |
SEE | 0.2 | 0.46 | 0.12 | 0.39 |
F value | 204 | 43 | 232 | 46 |
BS r2 | 0.98 | 0.94 | 0.98 | 0.97 |
BS SD | 0.15 | 0.32 | 0.1 | 0.14 |
r2pred | 0.59 | 0.58 | 0.56 | 0.59 |
Influence of different fields (%) | ||||
S | 59 | 50 | 67 | 42 |
E | 41 | - | 33 | - |
H | - | 50 | - | 58 |
Compounds | R1 | R2 | R3 | Predicted Activity (pIC50) | |
---|---|---|---|---|---|
c-KIT | PDGFRα | ||||
Compound D18 | H | 10.4 | 8.3 | ||
Compound D23 | CH3 | 10.1 | 8.2 | ||
Compound D25 | CH3 | 10.5 | 8.1 | ||
Compound D28 | CH3 | 9.6 | 8.4 | ||
Compound D32 | CH3 | 9.1 | 8.3 | ||
Compound D39 | H | 10.3 | 8.1 | ||
Compound D44 | H | 10.2 | 8.3 | ||
Compound D45 | H | 9.3 | 8.1 |
Complexes (Designed Compounds–Receptor) | Van der Waals (kJ/Mol) | Electrostatics (kJ/Mol) | Polar Solvation (kJ/Mol) | SASA (kJ/Mol) | Total Binding Energy (kJ/Mol) |
---|---|---|---|---|---|
D18–c-KIT | −272 | −57 | 218 | −28 | −139 |
D18–PDGFRα | −282 | −57 | 224 | −27 | −142 |
D23–c-KIT | −287 | −48 | 242 | −29 | −122 |
D23–PDGFRα | −286 | −36 | 212 | −28 | −138 |
D28–c-KIT | −278 | −62 | 242 | −27 | −126 |
D28–PDGFRα | −289 | −38 | 227 | −29 | −129 |
D32–c-KIT | −271 | −53 | 229 | −27 | −122 |
D32–PDGFRα | −283 | −44 | 224 | −28 | −130 |
D39–c-KIT | −268 | −65 | 212 | −26 | −148 |
D39–PDGFRα | −274 | −48 | 200 | −26 | −150 |
D44–c-KIT | −262 | −56 | 216 | −25 | −129 |
D44–PDGFRα | −261 | −42 | 209 | −26 | −120 |
D45–c-KIT | −262 | −76 | 244 | −26 | −121 |
D45–PDGFRα | −274 | −58 | 215 | −26 | −143 |
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Keretsu, S.; Ghosh, S.; Cho, S.J. Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors. Int. J. Mol. Sci. 2020, 21, 8232. https://doi.org/10.3390/ijms21218232
Keretsu S, Ghosh S, Cho SJ. Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors. International Journal of Molecular Sciences. 2020; 21(21):8232. https://doi.org/10.3390/ijms21218232
Chicago/Turabian StyleKeretsu, Seketoulie, Suparna Ghosh, and Seung Joo Cho. 2020. "Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors" International Journal of Molecular Sciences 21, no. 21: 8232. https://doi.org/10.3390/ijms21218232