Volume 15, Issue 3 (Summer 2026)
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Research code: 4010280
Ethics code: IR.HUMS.REC.1401.216
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Haghshenas Hafshjani R, Aghajani M, Abbasi M. Using bioinformatics methods to predict DNA topoisomerase II inhibitors for cancer treatment. aumj 2026; 15 (3) : 5
URL: http://aums.abzums.ac.ir/article-1-1981-en.html
URL: http://aums.abzums.ac.ir/article-1-1981-en.html
1- Student Research Committee, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
2- Department of Pharmaceutical Chemistry, School of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. ,mabbasi@hums.ac.ir
2- Department of Pharmaceutical Chemistry, School of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. ,
Abstract: (21 Views)
Introduction: Topoisomerase enzymes play a pivotal role in DNA metabolism by regulating DNA topology during essential cellular processes, including DNA replication, transcription, recombination, and chromosome segregation. Consequently, the identification and development of selective topoisomerase inhibitors have emerged as important strategies in the discovery and development of novel anticancer agents. In the present study, a series of structurally diverse multiring compounds was designed, and their potential inhibitory activities against DNA topoisomerase II were systematically investigated using a comprehensive in silico approach.
Methods: Following preparation of the target protein structure, a library of 349 compounds belonging to the pyrimido[1,2-a]benzimidazole class was designed and subjected to a multistage virtual screening workflow. Initial molecular docking and screening were performed using PyRx software, followed by more detailed molecular docking analyses using AutoDock. Subsequently, the binding free energies of the selected ligand–protein complexes were estimated using the molecular mechanics/generalized Born surface area (MM-GBSA) approach. Based on the results obtained from the successive screening stages, the most promising compound was selected for further molecular dynamics (MD) simulation and compared with the corresponding reference compound to evaluate the stability and dynamic behavior of the ligand–protein complex. The study was approved by the Ethics Committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1401.216).
Results: At each stage of the virtual screening process, the obtained docking and energetic parameters were compared with those of the reference compound. Among the evaluated compounds, compound 76 demonstrated the most favorable binding free energy according to the MM-GBSA calculations, with a value of −33.097 kcal/mol, compared with −24.690 kcal/mol for the reference compound. Based on its superior predicted binding affinity, compound 76 was identified as the most promising candidate for further investigation. Molecular dynamics simulation of compound 76 and the reference compound demonstrated favorable structural stability of the selected ligand–protein complex throughout the simulation period, supporting the potential stability of its interaction with the target enzyme.
Conclusion: The findings of this computational study suggest that pyrimido[1,2-a]benzimidazole derivatives may represent promising structural scaffolds for the development of DNA topoisomerase II inhibitors. Structure–activity analysis indicated that incorporation of an electron-withdrawing substituent at the meta position of the R2 moiety on the pyrimido[1,2-a]benzimidazole scaffold may favor the formation of compounds with suitable predicted inhibitory activity against DNA topoisomerase II. In particular, compound 76 exhibited a more favorable predicted binding free energy and stable molecular dynamics behavior compared with the reference compound. These findings provide a computational basis for the further structural optimization and experimental evaluation of pyrimido[1,2-a]benzimidazole derivatives as potential anticancer agents targeting DNA topoisomerase II.
Methods: Following preparation of the target protein structure, a library of 349 compounds belonging to the pyrimido[1,2-a]benzimidazole class was designed and subjected to a multistage virtual screening workflow. Initial molecular docking and screening were performed using PyRx software, followed by more detailed molecular docking analyses using AutoDock. Subsequently, the binding free energies of the selected ligand–protein complexes were estimated using the molecular mechanics/generalized Born surface area (MM-GBSA) approach. Based on the results obtained from the successive screening stages, the most promising compound was selected for further molecular dynamics (MD) simulation and compared with the corresponding reference compound to evaluate the stability and dynamic behavior of the ligand–protein complex. The study was approved by the Ethics Committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1401.216).
Results: At each stage of the virtual screening process, the obtained docking and energetic parameters were compared with those of the reference compound. Among the evaluated compounds, compound 76 demonstrated the most favorable binding free energy according to the MM-GBSA calculations, with a value of −33.097 kcal/mol, compared with −24.690 kcal/mol for the reference compound. Based on its superior predicted binding affinity, compound 76 was identified as the most promising candidate for further investigation. Molecular dynamics simulation of compound 76 and the reference compound demonstrated favorable structural stability of the selected ligand–protein complex throughout the simulation period, supporting the potential stability of its interaction with the target enzyme.
Conclusion: The findings of this computational study suggest that pyrimido[1,2-a]benzimidazole derivatives may represent promising structural scaffolds for the development of DNA topoisomerase II inhibitors. Structure–activity analysis indicated that incorporation of an electron-withdrawing substituent at the meta position of the R2 moiety on the pyrimido[1,2-a]benzimidazole scaffold may favor the formation of compounds with suitable predicted inhibitory activity against DNA topoisomerase II. In particular, compound 76 exhibited a more favorable predicted binding free energy and stable molecular dynamics behavior compared with the reference compound. These findings provide a computational basis for the further structural optimization and experimental evaluation of pyrimido[1,2-a]benzimidazole derivatives as potential anticancer agents targeting DNA topoisomerase II.
Article number: 5
Keywords: DNA Topoisomerase II, Molecular Docking, Molecular Dynamics Simulation, MM-GBSA, Pyrimido[1, 2-a]benzimidazole
Type of Study: Research |
Subject:
Special
Received: 2025/11/28 | Accepted: 2026/09/10 | Published: 2026/09/22
Received: 2025/11/28 | Accepted: 2026/09/10 | Published: 2026/09/22
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