Theoretical studies on benzimidazole and imidazo[1,2-a]pyridine derivatives as Polo-like kinase 1 (Plk1) inhibitors: Pharmacophore modeling, atom-based 3D-QSAR and molecular docking approach

Molecular modeling studies were carried out on a series of benzimidazole and imidazo[1,2-a]pyridines as Plk1 inhibitors. Based on the pharmacophore model, we obtained a five-featured hypothesis AADRR, with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic rings. An atom-based 3D-QSAR model was predicted for 36 training set (R2 = 0.9475, SD = 0.1927, F = 99.3) and nine test set (Q2 = 0.6519, RMSE = 0.4044, Pearson R = 0.834) compounds using a pharmacophore-based alignment. From these results, AADRR pharmacophore feature was chosen as the best common pharmacophore hypothesis, whereas the atom-based 3D-QSAR results explain the importance of hydrophobic and electron-withdrawing features for the most active compound 32. The dataset molecules were docked into the active site of Plk1, which shows acceptable hydrogen bond interactions with residues Cys133, Asp194, Glu131, Lys82 and Glu140 and also shows further hydrogen bond interactions with hydrophobic residues Cys67, Leu59 and Arg136. These results can be helpful for further design of novel Plk1 inhibitors.