Structure-based discovery of new polo-like kinase 1 (PLK1) inhibitors as potential anticancer agents via docking-based comparative intermolecular contacts analysis (dbCICA)

Polo-like kinase 1 (PLK1) plays vital roles in mitotic activities including G2/M transition, mitotic entry, and cytokinesis. PLK1 overexpression was observed in cancers and associated with poor prognosis. PLK1 inhibition was proven to hamper cancer hallmarks. In this research, a computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was employed to discover new PLK1 inhibitors. Eighty-two reported PLK1 inhibitors were fitted into the binding-pocket of a PLK1 crystallographic structure to specify their finest possible docking configurations. Optimal dbCICA models were utilized to create pharmacophores that were assessed by receiver operating characteristic (ROC) analysis and were employed for in-silico virtual screening of the National Cancer Institute database. The bioactivities of captured hits were evaluated via fluorescence-based kinase bioassay. Two promising hits were identified; 89 (NCI 37190) and 103 (NCI 1012) scored IC50 values of 6.30 and 19.1 μM, respectively.