Title:Structure-Based Virtual Screening Identifying Novel FOXM1 Inhibitors as the Lead Compounds for Glioblastoma
Volume: 19
Author(s): Kumari Swati*, Rashi Srivastava, Kirti Agrawal, Siva Prasad Panda, Anand Parkash, Dhruv Kumar and Hailiang Chen
Affiliation:
- Department of Biotechnology, School of Life Science, Mahatma Gandhi Central University, Motihari, Bihar, 845401, India
Keywords:
Glioblastoma multiform (GBM), cancer stem cells (CSCs), molecular docking, molecular dynamics simulation, in silico, phytochemical screening.
Abstract: 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 for screening a hundred naturally occurring
compounds capable of targeting the FOXM1 protein. Through molecular docking analysis and
pharmacokinetic profiling, five compounds were found to be 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
have the ability to induce senescence in GBM stem cells. These findings contribute to the development
of structure-based designing strategies for FOXM1 inhibitors and innovative therapeutic approaches
for the treatment of Glioblastoma.
