New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
Abstract
:1. Introduction
Rationale
2. Results and Discussion
2.1. In Silico Studies
2.1.1. Molecular Docking against Wild and Mutant EGFR
2.1.2. MD Simulations
2.1.3. MM-GBSA
2.1.4. Protein–Ligand Interaction Profiler (PLIP) Studies
2.1.5. DFT
Geometry Optimization
Frontier Molecular Orbital (FMO) Analysis
Global Reactive Indices and Total Density of State (TDOS)
Surface Potential Mapping
2.1.6. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Profiling Study
2.1.7. In Silico Toxicity Studies
2.2. Chemistry
2.3. Biological Evaluation
2.3.1. EGFR Inhibition
2.3.2. Cytotoxicity and Safety
2.3.3. Cell Cycle Analysis and Apoptosis Assay
3. Experimental
3.1. In Silico Studies
3.1.1. Docking Studies
3.1.2. MD Simulations
3.1.3. MM-GBSA
3.1.4. DFT
3.1.5. ADMET Studies
3.1.6. Toxicity Studies
3.2. Chemistry
Synthesis of Compound XI
3.3. Biological Studies
3.3.1. In Vitro Egfr Inhibition
3.3.2. In Vitro Antiproliferative Activity
3.3.3. Safety Assay
3.3.4. Cell Cycle Analysis and Apoptosis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Cluster Number | H-Is | Amino Acids in EGFR | H-Bs | Amino Acids in EGFR |
---|---|---|---|---|
C1 | 1 | F832 | 3 | Lys721-Thr830-Asp831 |
C2 | 4 | Leu764-Thr766-Phe832-Leu834 | 2 | Lys721-Asp831 |
C3 | 3 | Leu764-Phe832-Leu834 | 2 | Lys721-Thr830 |
IP | EA | μ (eV) | χ (eV) | η (eV) | σ (eV) | ω (eV) | µ (D) | TE (eV) | ∆Nmax | ∆E (eV) |
---|---|---|---|---|---|---|---|---|---|---|
−1.512 | −6.607 | −4.059 | 4.059 | −2.548 | −0.393 | −20.987 | 5.816 | −30469.8 | −1.593 | 20.987 |
Comp. | FDA Rodent Carcinogenicity (Mouse-Male) | Carcinogenic Potency TD50 (Mouse) a | Ames Mutagenicity | Rat Maximum Tolerated Dose (Feed) b | Rat Oral LD50 b | Rat Chronic LOAEL b | Skin Irritancy | Ocular Irritancy |
---|---|---|---|---|---|---|---|---|
The designed compound | Non-Carcinogen | 70.942 | Non-Mutagen | 0.024 | 1.575 | 0.039 | Non-Irritant | Mild |
Erlotinib | 39.771 | 0.083 | 0.662 | 0.036 |
Comp. | In Vitro Cytotoxicity IC50 (µM) a | A549 (SI) | HCT-116 (SI) | EGFR, IC50 (nM) | ||
---|---|---|---|---|---|---|
A549 | HCT-116 | WI-38 | ||||
Compound XI | 21.99 | 22.02 | 49.44 | 2.2 | 2.2 | 17.23 |
Erlotinib | 6.73 | 16.35 | 31.17 | 4.6 | 1.9 | 5.91 |
Sample | Cell Cycle Distribution (%) a | |||
---|---|---|---|---|
% Sub-G1 | % G1 | % S | % G2/M | |
A549 | 0.87 ± 0.35 | 43.47 ± 3.99 | 43.56 ± 2.31 | 12.10 ± 2.04 |
Compound XI/A549 | 0.80 ± 0.17 | 16.01 ± 5.00 | 63.35 ± 2.50 * | 19.84 ± 2.69 |
Sample | Viable a (Left Bottom) | Apoptosis a | Necrosis a (Left Top) | |
---|---|---|---|---|
Early (Right Bottom) | Late (Right Top) | |||
A549 | 99.44 ± 0.46 | 0.05 ± 0.02 | 0.49 ± 0.46 | 0.02 ± 0.01 |
Compound XI/A549 | 32.55 ± 2.98 | 24.02 ± 1.52 ** | 41.70 ± 1.76 ** | 1.73 ± 0.30 |
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Elkaeed, E.B.; Yousef, R.G.; Elkady, H.; Alsfouk, A.A.; Husein, D.Z.; Ibrahim, I.M.; Metwaly, A.M.; Eissa, I.H. New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies. Molecules 2022, 27, 5859. https://doi.org/10.3390/molecules27185859
Elkaeed EB, Yousef RG, Elkady H, Alsfouk AA, Husein DZ, Ibrahim IM, Metwaly AM, Eissa IH. New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies. Molecules. 2022; 27(18):5859. https://doi.org/10.3390/molecules27185859
Chicago/Turabian StyleElkaeed, Eslam B., Reda G. Yousef, Hazem Elkady, Aisha A. Alsfouk, Dalal Z. Husein, Ibrahim M. Ibrahim, Ahmed M. Metwaly, and Ibrahim H. Eissa. 2022. "New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies" Molecules 27, no. 18: 5859. https://doi.org/10.3390/molecules27185859