Probing Binding Modes of Small Molecule Inhibitors to the Polo-Box Domain of Human Polo-like Kinase 1

Purpurogallin (PPG, 2) and poloxin (3) have been reported as inhibitors of the polo-box domain (PBD) of human polo-like kinase 1. However, our experimental results demonstrated that PPG, but not poloxin, binds to the phospho-binding pocket of the PBD, suggesting that their modes of PBD inhibition are distinct. Induced fit docking analyses led us to propose that PPG fills the SpT pocket via pi-pi stacking and hydrogen-bonding interactions, thus providing a rationale for designing novel PBD inhibitors. In contrast, poloxin may fill a different site present near the SpT pocket by forming a covalent bond with a nucleophilic Cys residue.