Computational Analysis of Pyridopyrimidine-based Polo Like Kinase 2 (PLK2) Inhibitors: Examining the Structural Basis for Anticancer Activity

Background: Polo like kinase 2 (PLK2) has been reported as a new target for developing novel anticancer drugs. Here, three-dimensional quantitative structure-activity relationship (3D-QSAR), docking and molecular dynamics (MD) simulation studies were carried out on 70 pyridopyrimidine derivatives to focus on the structural necessities of potent PLK2 inhibitors. Method: An optimal CoMFA model with cross-validated correlation coefficient (q2) of 0.588 and non-cross-validated correlation coefficient (r2) of 0.812 was obtained through 3D-QSAR modeling. The predicted correlation coefficients (r2 pred) of 0.534 and validation result from bootstrapping analysis and progressive scrambling indicated the predictability and reliability of the model. Results and Conslusion: 3D-QSAR analysis demonstrated that inhibitory activities of these compounds are highly influenced by steric and electrostatic properties. Docking and MD simulations were used for inspecting interactions of PLK2 with inhibitors. Ligand-binding residues such as Leu88, Val143, Leu159, Cys162, Arg165 and Phe212 were identified at the binding site of PLK2. The binding interaction pattern observed during MD simulation was in accordance with the docking study. Present work offers insights about the structural requirements for PLK2 inhibition which can be exploited for the development of novel PLK2 inhibitors.