Drug design and molecular docking simulations of Polo-like kinase 1 inhibitors based on QSAR study

Abstract

In this study, the structure and activity relationship of 39 Plk1 inhibitors was explored by the three-dimensional quantitative structure–activity relationship (3D-QSAR) and hologram quantitative structure–activity relationship (HQSAR). The cross-validation correlation coefficient (q²) and non-cross-validation correlation coefficient (r²) of the topomer CoMFA model were 0.501 and 0.977, respectively. The most effective HQSAR model was obtained using the q² value of 0.537, the r² value of 0.815, and the best hologram length value of 199 using atoms and bonds as fragment distinctions. The results showed that the models not only had good estimation stability but also good prediction capability. Topomer Search was employed to virtually screen lead-like compounds in the ZINC database. As a result, 10 new compounds were designed as potential Plk1 inhibitors. Docking simulation was carried out to further investigate possible binding modes of compounds into the active site of the protein (PDB code: 6GY2). This study showed extensive interactions between Plk1 inhibitors and residues of LEU491, ASN533, TRP414 HIS538 and ARG557 in the active site. These results can provide useful insight for the design of potent Plk1 inhibitors.