Identification of novel potent peptide inhibitors targeting the polo-box domain of PLK1: structure-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics study and biological evaluation

Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1–5) targeting the polo box domain (PBD) of PLK1 through an integrated virtual screening strategy. MST assays confirmed that PLs 1–5 had strong binding affinity for PLK1, especially PL-1 (Kd = 3.11 ± 0.05 nM). Meanwhile, the kinase selectivity assay showed that the PL-1 had no significant inhibitory effects on a panel of other kinases. Molecular dynamics simulation further demonstrated the structural stability of PL-1 and PLK1 complex. Notably, PL-1 displayed potent antiproliferative efficacy against U266 multiple myeloma cells (IC50 = 0.09 ± 0.01 µM). PL-1 showed high intracellular uptake capacity. In addition, PL-1 exhibited good biostability in human serum and liver microsomes. Taken together, PL-1 is a potent and highly selective antitumor agent with considerable therapeutic promise for multiple myeloma.