Hightroughput structure-based virtual screening to select new inhibitory chemical compound(s) against FOXM1 transcription factor with its DNA target

As an important transcription factor, FOXM1 involves in various functions including the control of expression of several genes, the transition of cells into dividing phase, angiogenesis, migration and so on, and its overexpression has been reported in the different types of cancers. Therefore, this protein is a putative drug target in cancer therapy. Hitherto, many compounds and medicines have been targeted FOXM1 including FDI-6 and RCM-1 whose functions are the inhibition of FOXM1-DNA interactions. In this study, in order to inhibit FOXM1-DNA complex formation, in-vitro subset of the ZINC database was evaluated computationally. To achieve this purpose, ligand-binding pockets on the protein were explored firstly by running of MDpocket algorithm. Before computation of affinity binding energy of the compounds to the predicted pockets, the libraries (circa 260000 compounds) were screened using FAF-drugs4 web server based on the physicochemical properties. Afterwards, the passed compounds were docked on the predicted pockets of FOXM1 using AutoDock-VINA. The screening process was planned according to the affinity binding energy, structural alerts and toxic-free groups. Accordingly, the three compounds acquired the passing score with approximately the same docking energy. To differentiate and ranking of the selected compounds, the MM/PBSA approach was applied on the three ligand-FOXM1 complexes and finally, 1-Hydroxypyrene β-D-Glucuronide was picked out based on its binding free energy. The introduced ligand in this study is the promising novel hit molecule, interrupting FOXM1 interactions with its cognate DNA. However, more experimental efforts need to be performed for recognition of the discovered ligand as lead compound.