Identification of CHK1 Kinase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking

Abstract

The checkpoint kinase, CHK1 plays an important role in repairing DNA damage induced by genotoxic agents for cancer treatment, which renders the cells resistant to such treatment modalities. Therefore, its inhibition appeared as a highly attractive strategy to re-sensitize cancer cells to the DNA damaging chemo and radiotherapies. In this study, a structure-based drug design approach was employed to identify potential ATP competitive CHK1 inhibitors. To this end, 3 crystal structures of CHK1 in complex with ATP competitive inhibitors were utilized to generate structure-based pharmacophore models that were subsequently used for virtual screening of commercial databases. Retrieved hits were filtered, then they were docked into the binding site of the enzyme and the free binding energies of the top-ranked docked hits were calculated. Based on the in silico results, 10 compounds were selected and their CHK1 inhibitory potential was evaluated in vitro. Noteworthy, in this exploratory study compounds 7 and 9 showed moderate but significant inhibition of the catalytic activity of the CHK1 enzyme. These two compounds were identified as promising hits worthy of further optimization towards designing better leads with drug like properties as potential competitive CHK1 inhibitors.