Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles
Abstract
:1. Introduction
2. Methods
2.1. Protein Preparation
2.2. Preparation of the Ligand
2.3. Quantum-Polarized Ligand Docking (QPLD) and Design of New Aromatase Inhibitors
2.4. Glide Docking
2.5. ADME Prediction
2.6. Molecular Dynamics (MD) Simulation and Post-MD Binding Free Energy Calculation
2.7. Preparation of Gold Nanoparticles and DFT Calculations
3. Results
3.1. Molecular Docking and ADME Studies
3.2. Molecular Dynamics and Post-MD MM-GBSA Calculations
3.3. DFT Calculations
3.4. Molecular Docking with Human Off-Target Desmolase
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Name | Docking Scores (Kcal/mol) | Pi-Cation | Hydrogen Bond | Hydrophobic Interaction |
---|---|---|---|---|
Combine1 | −8.117 | ARG115 | ARG115 | ALA306/ALA307/MET303/VAL370/VAL373/ARG375/THR310/GLU302 |
Combine2 | −8.053 | ARG115 | ARG115 | PRO429/PHE430/ALA307/ALA306/ALA443 |
Combine3 | −8.83 | ARG115 | ARG115 | ARG435/MET364/ARG375/ARG435/VAL370/VAL373 |
Combine4 | −7.737 | ARG115 | GLN248 | ALA443/MET446/MET311/ILE442 |
Combine5 | −7.704 | ARG115 | ARG115/PHE430 | GLU302/TRP141/MET303 |
Combine6 | −7.411 | ARG115 | ARG115 | VAL373/GLU431 |
Combine7 | −7.342 | HEM601 | ARG115/ARG375/ARG345 | ILE398/PRO429/PHE430/PHE432 |
Combine8 | −7.324 | HEM601 | PHA430/ARG375 | PRO429/PHE430/ALA438/CYS437 |
Combine9 | −7.304 | ARG115 | MET303/ALA306/ALA307/VAL373/PHE430 | |
Combine10 | −7.287 | ARG145/PHE430 | ALA306/ALA307/ALA438/MET303/ILE398 | |
Combine11 | −7.119 | ARG115 | GLN428 | ALA438/GLU439/VAL370/VAL373 |
Combine12 | −7.09 | TRP141/ARG115 | PRO429/GLY431/ILE398 | |
Combine13 | −7.059 | ARG115 | ARG115 | ALA307/ALA438/ALA443/CYS437/PRO429/PHE430/GLY431 |
Combine14 | −7.041 | TRP141 | ALA306/ALA438/MET303/GLY430/GLY493/ARG375 | |
Letrozole | −4.109 | ARG115 | MET444/TRY441/TRY424/PHE430/PRO329/PHE427 | |
Testosterone | −5.322 | MET374 | ILE133, PHE134, PHE221, TRP224, ILE305, ALA306, VAL370, LEU372, VAL373, LEU477 |
Compound | QPlogPo/w a | QPlogS b | QPPCaco c | QPlogBB d | QPPMDCK e | %HOA | RoF g |
---|---|---|---|---|---|---|---|
Combine1 | 4.680 | −6.913 | 693.833 | −1.167 | 333.246 | 100 | 0 |
Combine2 | 4.639 | −7.150 | 463.709 | −1.395 | 215.576 | 100 | 0 |
Combine3 | 5.797 | −8.228 | 846.562 | −1.109 | 413.198 | 100 | 1 |
Combine4 | 4.444 | −7.404 | 497.569 | −1.291 | 232.640 | 100 | 0 |
Combine5 | 4.530 | −6.276 | 681.210 | −1.161 | 326.698 | 100 | 0 |
Combine6 | 4.715 | −6.897 | 349.469 | −1.527 | 158.792 | 100 | 0 |
Combine7 | 4.421 | −7.404 | 313.812 | −1.741 | 141.355 | 100 | 0 |
Combine8 | 4.345 | −6.140 | 602.982 | −1.321 | 286.342 | 100 | 0 |
Combine9 | 4.566 | −6.298 | 946.340 | −0.952 | 466.079 | 100 | 0 |
Combine10 | 4.763 | −7.227 | 444.186 | −1.340 | 205.783 | 100 | 0 |
Combine11 | 4.410 | −7.335 | 402.658 | −1.369 | 185.069 | 100 | 0 |
Combine12 | 4.397 | −5.987 | 817.738 | −1.009 | 398.012 | 100 | 0 |
Combine13 | 4.630 | −7.118 | 466.185 | −1.387 | 216.821 | 100 | 0 |
Combine14 | 4.117 | −5.968 | 437.232 | −1.383 | 202.303 | 100 | 0 |
Letrozole | 1.459 | −3.693 | 138.864 | −1.570 | 58.559 | 73.838 | 0 |
Compound | MM-GBSA Free Binding Energy (kcal/mol) |
---|---|
Combine1 | −68.9075 ± 5.304 |
Combine2 | −63.5514 ± 4.219 |
Combine3 | −66.2378 ± 5.1799 |
Letrozole | −44.3891 ± 8.014567 |
Complex | Interact Atom | E(UB3LYP) | Dipole Moment | Zero Energy |
---|---|---|---|---|
Complex1 | Nitrogen47 | −1932.195781 | 7.401879 | −1931.767112 |
Complex2 | Oxygen45 | −1932.163889 | 5.534319 | −1931.736428 |
Complex3 | Nitrogen30 | −1932.209405 | 14.785182 | −1931.780390 |
Complex4 | Nitrogen3 | −1932.197730 | 8.697839 | −1931.769055 |
Complex5 | Nitrogen5 | −1932.191763 | 10.960059 | −1931.763301 |
Complex6 | Nitrogen1 | −1932.201165 | 6.402050 | −1931.772674 |
Combine1 | - | −1390.215008 | 6.376844 | −1389.789215 |
Gold | - | −541.930470 | 0.00 | −541.929251 |
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Edris, A.; Abdelrahman, M.; Osman, W.; Sherif, A.E.; Ashour, A.; Garelnabi, E.A.E.; Ibrahim, S.R.M.; Bafail, R.; Samman, W.A.; Ghazawi, K.F.; et al. Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles. Metabolites 2023, 13, 583. https://doi.org/10.3390/metabo13050583
Edris A, Abdelrahman M, Osman W, Sherif AE, Ashour A, Garelnabi EAE, Ibrahim SRM, Bafail R, Samman WA, Ghazawi KF, et al. Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles. Metabolites. 2023; 13(5):583. https://doi.org/10.3390/metabo13050583
Chicago/Turabian StyleEdris, Alaa, Mohammed Abdelrahman, Wadah Osman, Asmaa E. Sherif, Ahmed Ashour, Elrashied A. E. Garelnabi, Sabrin R. M. Ibrahim, Rawan Bafail, Waad A. Samman, Kholoud F. Ghazawi, and et al. 2023. "Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles" Metabolites 13, no. 5: 583. https://doi.org/10.3390/metabo13050583