Abstract
The polo-box domain of polo-like kinase 1 (PLK1-PBD) is proved to have crucial roles in cell proliferation. Designing PLK1-PBD inhibitors is challenging due to their poor cellular penetration. In this study, we applied a virtual screening workflow based on a combination of structure-based pharmacophore modeling with molecular docking screening techniques, so as to discover potent PLK1-PBD peptide inhibitors. The resulting 9 virtual screening peptides showed affinities for PLK1-PBD in a competitive binding assay. In particular, peptide 5 exhibited an approximately 100-fold increase in inhibitory activity (IC50 = 70 nM), as compared with the control poloboxtide. Moreover, cell cycle experiments indicated that peptide 5 effectively inhibited the expression of p-Cdc25C and cell cycle regulatory proteins by affecting the function of PLK1-PBD, thereby inducing mitotic arrest at the G2/M phase. Overall, peptide 5 can serve as a potent lead for further investigation as PLK1-PBD inhibitors.
Highlights
Cancer is a highly fatal disease characterized by uncontrolled cell proliferation, which has led to the death of millions of people
The centrosome is an important organelle in the cell cycle process, which is responsible for the separation of genetic material, and its deregulation is related to the appearance of cancer [2]
Polo-like kinases (PLKs) are a subfamily of serine–threonine protein kinases that consist of multiple isoforms (PLK1 to PLK4), and play crucial roles in centrosome amplification [3,4,5]
Summary
Cancer is a highly fatal disease characterized by uncontrolled cell proliferation, which has led to the death of millions of people. 9.6 million people died from cancer in 2018 and. Among the PLKs, PLK1 is an essential regulator for the maturation of the centrosome and previous studies have shown that it is overexpressed in a wide range of cancers, which makes it an attractive target for anticancer drug design [5,6,7]. Targeting PLK1-PBD helps to avoid the selectivity issue of ATP competitive inhibitors resulting from the conservative structure of the kinase binding site, because the PBD is featured only for the PLK1 family [9]. It is difficult for small molecules to regulate this process, owing to the large interfaces between proteins [10]. Some phosphopeptide inhibitors of PLK1-PBD have been synthesized based on the fact that the PBD can bind to the serine- or threonine-phosphorylated peptides (p-S/T motif) of Cdc25C [13,14]
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