Computational Investigation of the Interaction of Large-scale Plant and Animal-Derived Natural Secondary Metabolites with FOXM1

FOXM1, a transcription factor from the Forkhead box family, serves as a crucial proto-oncogene that plays a role in cancer advancement, spread to distant sites, and resistance to chemotherapy across various human malignancies. The development of selective and therapeutically efficient FOXM1 inhibitors remains a significant challenge in the field. This study employed a multi-step computational approach to identify novel small-molecule compounds that target the DNA-binding domain (DBD) of FOXM1. A structure-guided virtual screening process was conducted using an extensive chemical compound database, evaluated against the crystallographic structure of FOXM1’s DNA-binding domain (PDB ID: 3G73). The top-ranking compounds underwent preliminary 10-nanosecond evaluations, subsequently followed by comprehensive 100-nanosecond molecular dynamics (MD) simulations. The binding affinities of the most thermodynamically stable protein-ligand complexes were determined through MM/GBSA calculations. The preliminary computational screening revealed 21 compounds that exhibited docking scores superior to -9.1 kcal/mol. Following 10 ns MD simulations, five compounds were selected, and 100 ns MD simulations confirmed the stable binding of these two compounds (comp_105546, comp_112458). MM/GBSA calculations identified comp_112458 as the most potent binder (-36.25±3.5 kcal/mol). This study successfully identified novel chemical scaffolds with high predicted affinity and stable binding modes against FOXM1, providing a strong foundation for the development of targeted anticancer agents. These promising computational results require validation through in vitro and in vivo studies.