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Molecular Docking Based Analysis to Elucidate the DNA Topoisomerase IIβ as the Potential Target for the Ganoderic
Kaushal K Sharma1, Brijendra Singh2, Somdutt Mujwar3
1Bioinformatics Infrastructure Facility DBT (Dr. APJ Abdul Kalam Central Instrumentation Facility), Jiwaji University Gwalior (M.P) 474001, India.
Introduction:
Intermediate covalent complex of DNA-Topoisomerase II enzyme is the most promising target of the anticancer drugs to induce apoptosis in cancer cells. Currently, anticancer drug and chemotherapy are facing major challenges i.e., drug resistance, chemical instability and, dose-limiting side effect. Therefore, in this study, natural therapeutic agents (series of Ganoderic acids) were used for the molecular docking simulation against Human DNATopoisomerase II beta complex (PDB ID:3QX3).
Methods:
Molecular docking studies were performed on a 50 series of ganoderic acids reported in the NCBI-PubChem database and FDA approved anti-cancer drugs, to find out binding energy, an interacting residue at the active site of Human DNA-Topoisomerase II beta and compare with the molecular arrangements of the interacting residue of etoposide with the Human DNA topoisomerase II beta. The autodock 4.2 was used for the molecular docking and pharmacokinetic and toxicity studies were performed for the analysis of physicochemical properties and to check the toxicity effects. Discovery studio software was used for the visualization and analysis of docked pose.
Results And Conclusion:
Ganoderic acids (GS-1, A and DM) were found to be a more suitable competitor inhibitor among the ganoderic acid series with appropriate binding energy, pharmacokinetic profile and no toxicity effects. The interacting residue (Met782, DC-8, DC-11 and DA-12) shared a chemical resemblance with the interacting residue of etoposide present at the active site of human topoisomerase II beta receptor.
Insights
Ganoderic acids GS-1, A, and DM show promise as anticancer agents by inhibiting DNA-Topoisomerase II beta. These natural compounds exhibit favorable binding energy, pharmacokinetics, and no toxicity, offering a potential alternative to conventional chemotherapy.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- The intermediate covalent complex of DNA-Topoisomerase II is a key target for anticancer drugs to induce apoptosis.
- Conventional anticancer drugs face challenges like drug resistance, instability, and side effects.
- Natural therapeutic agents offer a promising alternative to overcome these limitations.
Purpose of the Study:
- To investigate the potential of ganoderic acids as inhibitors of Human DNA-Topoisomerase II beta.
- To compare the binding efficacy and interactions of ganoderic acids with etoposide, a known inhibitor.
- To evaluate the pharmacokinetic and toxicity profiles of selected ganoderic acids.
Main Methods:
- Molecular docking simulations were performed on 50 ganoderic acids against Human DNA-Topoisomerase II beta (PDB ID: 3QX3).
- Autodock 4.2 was used for docking, with pharmacokinetic and toxicity studies conducted.
- Discovery Studio software facilitated visualization and analysis of docked poses and interactions.
Main Results:
- Ganoderic acids GS-1, A, and DM demonstrated superior inhibitory potential compared to other ganoderic acids.
- These compounds exhibited favorable binding energy and pharmacokinetic profiles.
- No significant toxicity effects were observed for GS-1, A, and DM.
Conclusions:
- Ganoderic acids GS-1, A, and DM are effective inhibitors of Human DNA-Topoisomerase II beta.
- Their binding interactions at the active site show resemblance to etoposide.
- These natural compounds represent a viable therapeutic strategy against cancer, overcoming limitations of current drugs.
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