Discovery of 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine as Novel Cyclin-dependent Kinases 4 and 6 Dual Inhibitors via 3D-QSAR and Molecular Simulation

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 molecular field analy-sis(CoMFA)and comparative molecular similarity indices analysis 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 q2 being 0.518 and r^(2) 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.Molecular docking confirmed the important residues for interactions.Molecular 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.

Comparison of survival prediction values of different scoring models for patients undergoing transjugular intrahepatic portal shunt:A multicenter retrospective study

Aim:The aim of this study is to compare the prognostic values of the Child–Pugh,integrated model for end‐stage liver disease(iMELD),albumin–bilirubin(ALBI),and Freiburg index of postsurvival(FIPS)scores in patients undergoing transjugular intrahepatic portosystemic shunt(TIPS).Methods:We conducted a multicenter retrospective study including patients who underwent TIPS by collecting data from several hospitals in southwest China between January 2014 and February 2021.We compared the performance of different scoring models for survival prediction in these patients.The performance of each scoring model was assessed via area under the receiver‐operating characteristic(AUROC)curve analysis.Results:The study included 378 TIPS patients(268 men,110 women;median age 52[interquartile range,45–60]years).Age;cirrhosis etiology;ascites severity;albumin levels;international normalized ratio;total bilirubin levels;sodium levels;and Child–Pugh,iMELD,ALBI,and FIPS scores were significant prognostic factors in cirrhotic patients who underwent TIPS.The Child–Pugh,iMELD,ALBI,and FIPS scores were all independent predictors of survival in TIPS patients.Survival analysis showed that all scoring models effectively stratified the prognostic risk of these patients.The Child–Pugh score was the best predictor of postoperative survival,followed by the ALBI and FIPS scores.The iMELD score was the worst predictor.The Child–Pugh,iMELD,ALBI,and FIPS scores predicted the 1‐year postoperative survival,with AUROC values of 0.832,0.677,0.761,and 0.745,respectively,and the 3‐year postoperative survival,with AUROC values of 0.710,0.668,0.721,and 0.658,respectively.The calibration curve showed that the Child–Pugh,ALBI,and FIPS models performed well in predicting 1‐and 3‐year survival,whereas the iMELD model was a poor predictor.Conclusions:The four scoring models can predict survival in cirrhotic patients after TIPS and can effectively stratify prognostic risk.The Child–Pugh score may be more suitable for predicting survival after TIPS in patients with liver cirrhosis.