Ligand-Based Pharmacophore Modeling, Atom-Based 3D-QSAR and Molecular Docking Studies on Substituted Thiazoles and Thiophenes as Polo-Like Kinase 1 (Plk1) Inhibitors

Polo-like kinase 1 (Plk1) is a decisive enzyme with its multifunctional activity in cell cycle progression especially mitosis. The over expression of Plk1 in broad spectrum of cancer types turns into a promising therapeutic target against cancer. In the present study, several ligand based pharmacophore models and atom based 3D-QSAR models have been generated using a series of 49 thiazole and thiophene derivatives with well prescribed Plk1 inhibitory activity. From the generated models, the AADRR hypothesis associated with an atom based 3D-QSAR model provided a satisfactory statistical significance containing predictive ability of 40 training set (R2 = 0.9539, SD = 0.1789, F = 113.8) and nine test set (Q2 = 0.4868, RMSE = 0.5333, Pearson R = 0.7114) molecules. The Hypothesis, AADRR explains the salient structural features of the molecules and the developed 3D-QSAR model points out the effect of hydrophobic groups, electron withdrawing groups and H-bond donor groups on Plk1 inhibition for the most active compound 47. The results were further supported by molecular docking studies, which explain the hydrogen bond interactions and binding mode of the ligands with Plk1. These molecular modelling results are expected to be useful for further design of active Plk1 inhibitors.