Auceliciclib

Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article, 3D-QSAR modeling including comparative mol. field anal. (CoMFA) and comparative mol. similarity indexes anal. fields (CoMSIA) was implemented on 52 dual CDK4/6 inhibitors.As a result, we obtained a pretty good 3D-QSAR model, which is CoMFACDK4 with q2 to be 0.543 and r 2 to be 0.967; CoMSIACDK4 with q 2 being 0.518 and r2 being 0.937; CoMFACDK6 with q2 to be 0.624 and r 2 to be 0.984; CoMSIACDK6 with q2 being 0.584 and r 2 being 0.975.Mol. docking confirmed the important residues for interactions.Mol. dynamics simulation further confirmed binding affinity with key residues of protein, such as Lys22, Lys35, Val96 for CDK4 and Lys43, His100, Val101 for CDK6 at the active sites.Then these results offered new directions to explore new inhibitors of CDK4/6.Finally, we designed 10 novel compounds with promising expected activity and ADME/T properties, and provided referable synthetic routes.