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Computational exploration of FOXM1 inhibitors for glioblastoma : an integrated virtual screening and molecular dynamics simulation study

Swati, Kumari ; Varma, Sudhir Rama ; Parameswari, R. P. ; Panda, Siva Prasad ; Agrawal, Mohit ; Prakash, Anand ; Kumar, Dhruv and Agarwal, Prasoon LU orcid (2024) In Journal of Biomolecular Structure and Dynamics
Abstract

In this study, a comprehensive investigation of a set of phytochemicals to identify potential inhibitors for the Forkhead box protein M1 (FOXM1) was conducted. FOXM1 is overexpressed in glioblastoma (GBM) cells and plays a crucial role in cell cycle progression, proliferation, and invasion. FOXM1 inhibitors have shown promising results in preclinical studies, and ongoing clinical trials are assessing their efficacy in GBM patients. However, there are limited studies on the identification of novel compounds against this attractive therapeutic target. To address this, the NPACT database containing 1,574 phytochemicals was used, employing a hierarchical multistep docking approach, followed by an estimation of relative binding free energy.... (More)

In this study, a comprehensive investigation of a set of phytochemicals to identify potential inhibitors for the Forkhead box protein M1 (FOXM1) was conducted. FOXM1 is overexpressed in glioblastoma (GBM) cells and plays a crucial role in cell cycle progression, proliferation, and invasion. FOXM1 inhibitors have shown promising results in preclinical studies, and ongoing clinical trials are assessing their efficacy in GBM patients. However, there are limited studies on the identification of novel compounds against this attractive therapeutic target. To address this, the NPACT database containing 1,574 phytochemicals was used, employing a hierarchical multistep docking approach, followed by an estimation of relative binding free energy. By fixing user-defined XP-dock and MM-GBSA cut-off scores of −6.096 and −37.881 kcal/mol, the chemical space was further narrowed. Through exhaustive analysis of molecular binding interactions and various pharmacokinetics profiles, we identified four compounds, namely NPACT00002, NPACT01454, NPACT00856, and NPACT01417, as potential FOXM1 inhibitors. To assess the stability of protein-ligand binding in dynamic conditions, 100 ns Molecular dynamics (MD) simulations studies were performed. Furthermore, Molecular mechanics with generalized Born and surface area solvation (MM-GBSA) based binding free energy estimations of the entire simulation trajectories revealed a strong binding affinity of all identified compounds towards FOXM1, surpassing that of the control drug Troglitazone. Based on extensively studied multistep docking approaches, we propose that these molecules hold promise as FOXM1 inhibitors for potential therapeutic applications in GBM. However, experimental validation will be necessary to confirm their efficacy as targeted therapies. Communicated by Ramaswamy H. Sarma.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
docking, FOXM1, GBM, MD simulation, MM-GBSA analysis
in
Journal of Biomolecular Structure and Dynamics
publisher
Adenine Press
external identifiers
  • pmid:38305824
  • scopus:85184184997
ISSN
0739-1102
DOI
10.1080/07391102.2024.2308772
language
English
LU publication?
yes
id
8da0af91-800a-4111-9709-a1a0085883c5
date added to LUP
2024-02-27 10:24:00
date last changed
2024-04-26 13:29:22
@article{8da0af91-800a-4111-9709-a1a0085883c5,
  abstract     = {{<p>In this study, a comprehensive investigation of a set of phytochemicals to identify potential inhibitors for the Forkhead box protein M1 (FOXM1) was conducted. FOXM1 is overexpressed in glioblastoma (GBM) cells and plays a crucial role in cell cycle progression, proliferation, and invasion. FOXM1 inhibitors have shown promising results in preclinical studies, and ongoing clinical trials are assessing their efficacy in GBM patients. However, there are limited studies on the identification of novel compounds against this attractive therapeutic target. To address this, the NPACT database containing 1,574 phytochemicals was used, employing a hierarchical multistep docking approach, followed by an estimation of relative binding free energy. By fixing user-defined XP-dock and MM-GBSA cut-off scores of −6.096 and −37.881 kcal/mol, the chemical space was further narrowed. Through exhaustive analysis of molecular binding interactions and various pharmacokinetics profiles, we identified four compounds, namely NPACT00002, NPACT01454, NPACT00856, and NPACT01417, as potential FOXM1 inhibitors. To assess the stability of protein-ligand binding in dynamic conditions, 100 ns Molecular dynamics (MD) simulations studies were performed. Furthermore, Molecular mechanics with generalized Born and surface area solvation (MM-GBSA) based binding free energy estimations of the entire simulation trajectories revealed a strong binding affinity of all identified compounds towards FOXM1, surpassing that of the control drug Troglitazone. Based on extensively studied multistep docking approaches, we propose that these molecules hold promise as FOXM1 inhibitors for potential therapeutic applications in GBM. However, experimental validation will be necessary to confirm their efficacy as targeted therapies. Communicated by Ramaswamy H. Sarma.</p>}},
  author       = {{Swati, Kumari and Varma, Sudhir Rama and Parameswari, R. P. and Panda, Siva Prasad and Agrawal, Mohit and Prakash, Anand and Kumar, Dhruv and Agarwal, Prasoon}},
  issn         = {{0739-1102}},
  keywords     = {{docking; FOXM1; GBM; MD simulation; MM-GBSA analysis}},
  language     = {{eng}},
  publisher    = {{Adenine Press}},
  series       = {{Journal of Biomolecular Structure and Dynamics}},
  title        = {{Computational exploration of FOXM1 inhibitors for glioblastoma : an integrated virtual screening and molecular dynamics simulation study}},
  url          = {{http://dx.doi.org/10.1080/07391102.2024.2308772}},
  doi          = {{10.1080/07391102.2024.2308772}},
  year         = {{2024}},
}