New Natural Compound Inhibitors of Checkpoint Kinase-1(CHK1) Based on Computational Study

Abstract As a malignant tumor of the ovary, the general treatment principle of ovarian cancer is surgical treatment, supplemented by chemotherapy, and some patients can use targeted drugs. Its treatment effect is relatively poor, so the prognosis is poor, the mortality rate is high. To contribute to drug design and refinement, ideal lead compounds with potential inhibitory effects on ATP-competitive CHK1 (Checkpoint kinase-1) inhibitors were downloaded from the drug library (ZINC15 database) and screened afterwards. The ATP-competitive CHK1 inhibitors were identified by using computer-aided virtual screening technology. We first calculated the LibDock score through the docking of proteins and molecules, and then analyzed the pharmacological and toxicological properties. Then, we performed precise docking of the small molecules selected in the above steps with CHK1 protein to analyze their docking mechanism and affinity. Next, we used molecular dynamics simulation to make a assessment if the ligand-CHK1 complex were stable in natural environment. As the result shown, ZINC000008214547 and ZINC000072103632 were proved to bind with CHK1 with a higher binding affinity and stability. Additionally, their toxicological analysis shows that they are less toxic and will not inhibit the activity of cytochrome P-450 2D6. In the simulation of molecular dynamics, we also found that ZINC000008214547-CHK1 and ZINC000072103632-CHK1 complexes’ potential energy were more favorable compared with reference ligand, Prexasertib. Not only that, the two complexes also showed better stability in the natural environment. So, all results elucidated that ZINC000008214547 and ZINC000072103632 were favorable lead inhibitors of CHK1 protein. ZINC000008214547 and ZINC000072103632 were safe and had the potential to inhibit CHK1 protein. They may contribute a solid foundation for the development of CHK1 target drug.