Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα
Abstract
:1. Introduction
2. Results and Discussion
2.1. Phenotypic Screening of Thiocarbohydrazones on Human Cancer Cell Lines
2.2. Similarity-Based Quest for Possible Targets: Human DNA Topoisomerase IIα
2.3. Thiosemicarbazide and Thiocarbohydrazone Binding to Topo IIα ATPase Domain Investigated with Molecular Simulations
2.4. In Silico Target Fishing of Thiocarbohydrazones and Assessment of Drug-Likeness
3. Materials and Methods
3.1. Chemistry
3.2. Biology
3.2.1. Cell Culture and Preparation of Solutions
3.2.2. Annexin V and Propidium Iodide Staining
3.2.3. Concentration–Response Curve Plotting
3.2.4. Cell Cycle Analysis
3.2.5. Caspase-8 and Caspase-9 Activities
3.2.6. Generation of Radical Oxygen Species in Mitochondria
3.2.7. Human DNA Topoisomerase IIα-Mediated Decatenation Assay
3.2.8. Human DNA Topoisomerase IIα-Mediated Relaxation Assay
3.2.9. Human DNA Topoisomerase IIα Cleavage Assay
3.2.10. Wheatgerm Topo I Unwinding ASSAY
3.3. Molecular Modeling
3.3.1. Molecular Docking Calculations
3.3.2. Molecular Dynamics Simulations
3.3.3. Analysis of the MD Trajectories
3.3.4. Pharmacophore Similarity Search and ADME-Tox Predictions
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Replica, Timeframe | Conformation |
Main Amino Acid Residues (Total Energy Decomposition ΔG in kcal/mol) | |
---|---|---|---|
Compound 2 | R1, 40–60 ns | CF1, bent | Asn95 (−3.21), Asn91 (−2.97), Asn120 (−1.79), Phe142 (−1.43), Ile141 (−1.29), Ile 217 (−0.96), Thr215 (−0.92), Gly166 (−0.85), Ala167 (−0.85), Ile125 (−0.84) |
R1, 100–120 ns | CF2, linear | Asn91 (−1.85), Asn95 (−1.79), Ile141 (−1.78), Ile125 (−1.65), Asn120 (−1.47), Ile217 (−0.90), Arg98 (−0.83), Asn163 (−0.83), Phe142 (−0.79), Gly164 (−0.72), Thr215 (−0.67) | |
TSC24 | 40–60 ns | restrained | Ile141 (−2.17), Phe142 (−1.82), Asn91 (−1.06), Ala92 (−0.94), Ile125 (−0.94), Ser148 (−0.86), Thr215 (−0.85), Ile217 (−0.84), Gly164 (−0.78), Ile88 (−0.77) |
160–180 ns | restrained | Ala92 (−1.86), Ile217 (−1.79), Ile125 (−1.49), Gly164 (−1.09), Phe142 (−0.99), Ile141 (−0.98), Thr215 (−0.92), Asn91 (−0.80), Ile88 (−0.68), Asn120 (−0.67) |
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Cvijetić, I.N.; Herlah, B.; Marinković, A.; Perdih, A.; Bjelogrlić, S.K. Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα. Pharmaceuticals 2023, 16, 341. https://doi.org/10.3390/ph16030341
Cvijetić IN, Herlah B, Marinković A, Perdih A, Bjelogrlić SK. Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα. Pharmaceuticals. 2023; 16(3):341. https://doi.org/10.3390/ph16030341
Chicago/Turabian StyleCvijetić, Ilija N., Barbara Herlah, Aleksandar Marinković, Andrej Perdih, and Snežana K. Bjelogrlić. 2023. "Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα" Pharmaceuticals 16, no. 3: 341. https://doi.org/10.3390/ph16030341