Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Data Collection—Sequence and Structure Details
2.2. Homology Modeling and Protein Structure Validation of UNG2 by Modeller, I-TASSER and AlphaFold
2.3. Intrinsically Disordered Region in UNG2 (AA 1–92)
2.4. Molecular Docking of FAM72A Protein and UNG2 Peptide (AA 1–45) by HPEPDOCK
2.5. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) Calculation
2.6. Carbon Distribution (CARd) Analysis
2.7. Amino Acid-Specific Mutations in FAM72A Protein-UNG2 (AA 1–45) Peptide Heterodimer (FAM72A F104A, F104R, F104N, F104G, and F104S)
2.8. Molecular Dynamics Simulation by GROMACS
2.9. Virtual Screening for Lead Molecule Identification against FAM72A Protein and UNG2 (AA 1–45) Peptide Mono/Heterodimer
2.10. Molecular Docking of FAM72A Protein and UNG2 (AA 1–45) Peptide Heterodimer and FAM72A Monomer with Small Chemical Molecules
3. Results and Discussion
3.1. Homology Modeling and Protein Structure Validation of UNG2 by Modeller, I-TASSER and AlphaFold
3.2. Intrinsically Disordered Region in N-Terminal UNG2 (AA 1–92)
3.3. FAM72A-UNG2 Interaction and Molecular Docking Study of FAM72A Protein and UNG2 (AA 1–45) Peptide by HPEPDOCK
3.4. Free Binding Energy Prediction on FAM72A Protein and UNG2 (AA 1–45) Peptide Heterodimer
3.5. AA-Specific Mutations in the FWMF Motif (AA 101–104) of FAM72A Affecting the FAM72A Protein and UNG2 (AA 1–45) Peptide Heterodimer Binding
3.6. Molecular Dynamic Simulation by GROMACS Validates AA-specific Mutations in the FWMF Motif (AA 101–104) of FAM72A Affecting FAM72A-UNG2 Heterodimer Binding
3.7. CARd Analysis
3.8. Lead Discovery and Chemical Docking—Interference with FAM72A-UNG2 Interaction and Activity
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Renganathan, S.; Pramanik, S.; Ekambaram, R.; Kutzner, A.; Kim, P.-S.; Heese, K. Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing. Cancers 2021, 13, 5870. https://doi.org/10.3390/cancers13225870
Renganathan S, Pramanik S, Ekambaram R, Kutzner A, Kim P-S, Heese K. Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing. Cancers. 2021; 13(22):5870. https://doi.org/10.3390/cancers13225870
Chicago/Turabian StyleRenganathan, Senthil, Subrata Pramanik, Rajasekaran Ekambaram, Arne Kutzner, Pok-Son Kim, and Klaus Heese. 2021. "Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing" Cancers 13, no. 22: 5870. https://doi.org/10.3390/cancers13225870