Computational basis for the design of PLK-2 inhibitors

Abstract

PLK-2 is a serine/threonine protein kinase and plays a crucial role in cell cycle regulation; due to its pivotal function, this enzyme is approved as cancer drug target. We used BI-2536 a PLK-1/PLK-2 inhibitor to build a pharmacophore model and applied in the virtual screening of ZINC database to retrieve new molecules that bind the active site of PLK-2 environment with a high fit value. The molecules that do not fit the enzyme active site environment were subjected to conformation enrichment by generation of conformations in the active site environment by molecular docking, and the molecules with new scaffold that did not pass into the active site from molecular docking were subjected to molecular pruning to delete bulky substituents that prevent the molecules from binding. Molecular docking was used to find the binding pose of the selected molecules into active site of PLK-2; all screened-in hit molecules make favorable non-bonding interactions with PLK-2 active site similar to the reference inhibitor. Molecular dynamics simulations, the binding free energy calculations of the complexes, and the stability of hydrogen bonding interactions further revealed the usefulness of these screened compounds as suitable hit molecules for inhibition of PLK-2.