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Updated: Jun 26, 2025
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Structure-Based Virtual Screening of Novel FOXM1 Inhibitors as Potential Compounds for Glioblastoma Treatment
Kumari Swati1, Rashi Srivastava2, Kirti Agrawal3
1Department of Biotechnology, School of Life Science, Mahatma Gandhi Central University, Motihari, Bihar, 845401, India.
Background:
Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM.
Objective:
In this research, the objective was to perform structure-based in silico screening with the aim of identifying natural compounds proficient in targeting the DNA-binding domain (DBD) of the FOXM1 protein.
Methods:
In this study, in silico tools were employed to screen a hundred naturally occurring compounds capable of targeting the FOXM1 protein. Through molecular docking analysis and pharmacokinetic profiling, five compounds were promising candidates for extensive interaction with the FOXM1 protein. Further, these compounds were validated for the stability of the FOXM1-natural compound complex using molecular dynamics (MD) simulations.
Results:
Four compounds, such as Withaferin A, Bryophyllin A, Silybin B, Sanguinarine and Troglitazone (control compound), emerged as promising candidates with substantial interactions with FOXM1, suggesting their potential as a protein inhibitor based on molecular docking investigations. After MD simulation analysis, the FOXM1- Bryophyllin A complex was found to maintain the highest stability, and the other three ligands had moderate but comparable binding affinities over a period of 100 ns.
Conclusion:
This study provides valuable insights into four promising FOXM1 inhibitors that can induce senescence in GBM stem cells. These findings contribute to developing structure-based designing strategies for FOXM1 inhibitors and innovative therapeutic approaches for treating Glioblastoma.
Insights
This study identified four natural compounds that inhibit FOXM1, a key protein in Glioblastoma stem cells. Bryophyllin A showed the most stable interaction, offering potential for new Glioblastoma treatments.
Area of Science:
- Oncology
- Biochemistry
- Computational Chemistry
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
- Cancer stem cells (CSCs) drive GBM's resistance to therapy and tumor progression.
- The transcription factor FOXM1 is implicated in GBM growth, metastasis, and treatment resistance.
Purpose of the Study:
- To identify natural compounds targeting the DNA-binding domain of FOXM1 using structure-based in silico screening.
- To discover novel inhibitors for FOXM1, a critical target in Glioblastoma.
Main Methods:
- In silico screening of 100 natural compounds against the FOXM1 protein.
- Molecular docking and pharmacokinetic profiling to identify potential binders.
- Molecular dynamics (MD) simulations to assess the stability of FOXM1-natural compound complexes.
Main Results:
- Four compounds (Withaferin A, Bryophyllin A, Silybin B, Sanguinarine) showed significant interactions with FOXM1.
- Bryophyllin A formed the most stable complex with FOXM1, confirmed by 100 ns MD simulations.
- Other identified compounds exhibited moderate binding affinities.
Conclusions:
- Identified four potential FOXM1 inhibitors with the capacity to induce senescence in GBM stem cells.
- Findings support structure-based drug design for FOXM1 inhibitors.
- These compounds represent novel therapeutic strategies for Glioblastoma treatment.
