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Natural Compound Dioscin Targeting Multiple Cancer Pathways through its High Affinity Binding to B Cell Lymphoma-2
Shweta Gulia1, Prakash Chandra1, Asmita Das1
1Department of Biotechnology, Delhi Technological University, Main Bawana Road, Delhi, 110042, India.
Objectives:
The study aimed to explore the crucial genes involved in cancer-related biological processes, including EMT, autophagy, apoptosis, anoikis, and metastasis. It also sought to identify common genes among the pathways linked to these biological processes, determine the level of Bcl-2 expression in various types of cancers, and find a potent inhibitor of Bcl-2 among natural compounds.
Methods:
Common genes involved in the pathways related to EMT, autophagy, apoptosis, anoikis, and metastasis were explored, and the level of the most frequently overexpressed gene that was Bcl-2, in various types of cancers was analyzed by gene expression analysis. A set of 102 natural compounds was sorted according to their docking scores using molecular docking and filtering. The top-ranked molecule was chosen for additional molecular dynamics (MD) simulation for 100 ns. Differential gene expression analysis was performed for Dioscin using GEO2R.
Results:
The study identified four common genes, Bcl-2, Bax, BIRC3, and CHUK, among the pathways linked to EMT, autophagy, apoptosis, anoikis, and metastasis. Bcl-2 was highly overexpressed in many cancers, including Acute Myeloid Leukemia, Diffuse large B cell lymphoma, and Thymoma. The Dioscin structure in the Bcl-2 binding site received the highest docking score and the most relevant interactions. Dioscin's determined binding free energy by MM/GBSA was -52.21 kcal/mol, while the same calculated by MM/PBSA was -9.18 kcal/mol. A p-value of less than 0.05 was used to determine the statistical significance of the analysis performed using GEO2R. It was observed that Dioscin downregulates Bcl-2, BIRC3, and CHUK and upregulates the pro-apoptotic protein Bax.
Conclusion:
The study concluded that Dioscin has the potential to act as a protein inhibitor, with a noteworthy value of binding free energy and relevant interactions with the Bcl-2 binding site. Dioscin might be a good alternative for targeting multiple cancer pathways through a single target.
Insights
This study identified common genes in cancer pathways and found that Dioscin downregulates Bcl-2, a key protein in many cancers. Dioscin shows potential as a natural inhibitor targeting multiple cancer pathways.
Area of Science:
- Oncology
- Computational Biology
- Pharmacology
Background:
- Cancer progression involves complex biological processes like epithelial-mesenchymal transition (EMT), autophagy, apoptosis, anoikis, and metastasis.
- Identifying common genes across these pathways is crucial for developing targeted therapies.
- Bcl-2 is frequently overexpressed in various cancers, making it a significant therapeutic target.
Purpose of the Study:
- To identify common genes involved in EMT, autophagy, apoptosis, anoikis, and metastasis.
- To analyze Bcl-2 expression levels in different cancer types.
- To discover a potent natural compound inhibitor of Bcl-2.
Main Methods:
- Gene expression analysis and pathway analysis were used to identify common genes.
- Molecular docking and molecular dynamics simulations were employed to screen natural compounds for Bcl-2 inhibition.
- Differential gene expression analysis (GEO2R) was performed for the identified compound, Dioscin.
Main Results:
- Four common genes (Bcl-2, Bax, BIRC3, CHUK) were identified across the studied cancer pathways.
- Bcl-2 was found to be highly overexpressed in Acute Myeloid Leukemia, Diffuse large B cell lymphoma, and Thymoma.
- Dioscin demonstrated significant binding affinity to Bcl-2, downregulating Bcl-2, BIRC3, and CHUK, while upregulating Bax.
Conclusions:
- Dioscin exhibits potential as a protein inhibitor targeting the Bcl-2 binding site.
- Dioscin's ability to interact with Bcl-2 and modulate key cancer-related genes suggests its therapeutic promise.
- Dioscin may serve as a valuable natural compound for targeting multiple cancer pathways via a single molecular target.
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