Untying the knot of transcription factor druggability: Molecular modeling study of FOXM1 inhibitors.
The FOXM1 protein is a relevant transcription factor involved in cancer cell proliferation. The direct or indirect inhibition of this protein's transcriptional activity by small molecule drugs correlates well with a potentially significant anti-cancer profile, making this macro molecule a promising drug target. There are a few drug molecules reported to interact with (and inhibit) the FOXM1 DNA binding domain (FOXM1-BD), causing downregulation of protein expression and cancer cell proliferation inhibition. Among these drug molecules are the proteasome inhibitor thiostrepton, the former antidiabetic drug troglitazone, and the new FDI-6 molecule. Despite their structural differences, these drugs exert a similar inhibitory profile, and this observation prompted us to study a possible similar mechanism of action. Using a series of molecular dynamics simulations and docking protocols, we identified essential binding interactions exerted by all three classes of drugs, among which, a π-sulfur interaction (between a His287 and a sulfur-containing heterocycle) was the most important. In this report, we describe the preliminary evidence suggesting the presence of a drug-binding pocket within FOXM1 DNA binding domain, in which inhibitors fit to dissociate the protein-DNA complex. This finding suggests a common mechanism of action and a basic framework to design new FOXM1 inhibitors.
['Tabatabaei-Dakhili|S Amirhossein|SA|', 'Aguayo-Ortiz|Rodrigo|R|', 'Domínguez|Laura|L|', 'Velázquez-Martínez|Carlos A|CA|']
D001665:Binding Sites D015195:Drug Design D000072278:Forkhead Box Protein M1 D006801:Humans D008024:Ligands D008958:Models, Molecular D008968:Molecular Conformation D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D015394:Molecular Structure D011485:Protein Binding D021281:Quantitative Structure-Activity Relationship D013883:Thiostrepton
FOXM1 Thiostrepton Troglitazone Thiazolidinediones