Study on Virtual Screening,Enzyme Inhibitory Activity and Metabolic Stability of PARP Inhibitors
Poly-ADP-ribose polymerase shows significant therapeutic effect on patients bearing BRCA mutations via the'synthetic lethality'strategy,and it has become an important target in cancer treatment.Several PARP inhibitors have been approved and marketed,greatly improved the current treatment status of ovarian cancer.However,the drug resistance and low subtype selectivity have attracted great attention from researchers.In this study,the Glide docking was used for virtual screening,and the hit compound Y041-8647 was found with potent PARP inhibitory activity(PARP1,IC50:1.4 μmol/L).In vitro metabolic stability investigation demonstrated that Y041-8647 exhibits excellent stability in artificial gastrointestinal fluids,plasma,and liver microsomes.Further molecular dynamics simulations elucidated the interaction patterns between Y041-8647 and the 7KK5 protein.In this research,compound Y041-8647 is identified as a lead candidate for subsequent modification,which provides novel insight into the development of novel PARP inhibitors.
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