3D-QSAR study of Chk1 kinase inhibitors based on docking

Checkpoint kinase 1 (Chk1), a kind of a serine/threonine protein kinase, plays a significant role in DNA damage-induced checkpoints. Chk1 inhibitors have been demonstrated to abrogate the S and G2 checkpoints and disrupt the DNA repair process, which results in immature mitotic progression, mitotic catastrophe, and cell death. Normal cells remain at the G1 phase via p53 to repair their DNA damages, and are less influenced by the abrogation of S and G2 checkpoint. Therefore, selective inhibitors of Chk1 may be of great therapeutic value in cancer treatment. In this paper, in order to understand the structure-activity relationship of macro-cyclic urea Chk1 inhibitors, a study combined molecular docking and 3D-QSAR modeling was carried out, which resulted in two substructure-based 3D-QSAR models, including the CoMFA model (r(2), 0.873; q(2), 0.572) and CoMSIA model (r(2), 0.897; q(2), 0.599). The detailed microscopic structures of Chk1 binding with inhibitors were performed by molecular docking. Two docking based 3D-QSAR models were developed (CoMFA with r(2), 0.887; q(2), 0.501; CoMSIA with r(2), 0.872; q(2), 0.520). The contour maps obtained from the 3D-QSAR models in combination with the docked binding structures would be helpful to better understand the structure-activity relationship. All the conclusions drawn from both the 3D-QSAR contour maps and molecular docking were in accordance with the experimental activity dates. The results suggested that the developed models and the obtained CHk1 inhibitor binding structures might be reliable to predict the activity of new inhibitors and reasonable for the future drug design.