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Exploring Potential Binding Modes of Small Drug-like Molecules to the Polo-Box Domain of Human Polo-like Kinase 1.

ABSTRACT: Purpurogallin (PPG) and Poloxin have been reported as inhibitors of the polo-box domain (PBD) of human polo-like kinase 1 (Plk1). 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 (IFD) 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.

SUBMITTER: Liao C

PROVIDER: S-EPMC2898210 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOver the years, a great deal of effort has been focused on the design and synthesis of potent, linear peptide inhibitors targeting the polo-like kinase 1 (Plk1), which is critically involved in multiple mitotic processes and has been established as an adverse prognostic marker for tumor patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain, and inhibiting the Plk1 polo-box domain has been considered as an approach to circumvent the specificity problems associated with inhibiting the conserved adenosine triphosphate-binding pocket. The polo-box domain consists of two different binding regions, such as the unique, broader pyrrolidine-binding pocket and the conserved, narrow, Tyr-rich hydrophobic channel, among the three Plk polo-box domains (Plks 1-3), respectively. Therefore, the studies that provide insights into the binding nature of the unique, broader pyrrolidine-binding pocket might lead to the development of selective Plk1-inhibitory compounds.Methodology/principal findingsIn an attempt to retain the monospecificity by targeting the unique, broader pyrrolidine-binding pocket, here, for the first time, a systematic approach was undertaken to examine the structure-activity relationship of N-terminal-truncated PLHSpTM derivatives, to apply a site-directed ligand approach using bulky aromatic and non-aromatic systems, and to characterize the binding nature of these analogues using X-ray crystallographic studies. We have identified a new mode of binding interactions, having improved binding affinity and retaining the Plk1 polo-box domain specificity, at the pyrrolidine-binding pocket. Furthermore, our data revealed that the pyrrolidine-binding pocket was very specific to recognize a short and bulky hydrophobic ligand like adamantane, whereas the Tyr-rich hydrophobic channel was specific with lengthy and small hydrophobic groups.Conclusion/significanceThe progress made using our site-directed ligands validated this approach to specifically direct the ligand into the unique pyrrolidine-binding region, and it extends the applicability of the strategy for discovering selective protein-protein interaction inhibitors.

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Exploring Potential Binding Modes of Small Drug-like Molecules to the Polo-Box Domain of Human Polo-like Kinase 1.

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