In order to investigate the inhibiting mechanism and obtain some helpful information for designing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship （3D-QSAR） and doc...In order to investigate the inhibiting mechanism and obtain some helpful information for designing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies have been performed on 45 pyrido[2,3-d] pyrimidine derivatives acting as Wee1 inhibitors. Two optimal 3D-QSAR models with significant statistical quality and satisfactory predictive ability were established, including the CoMFA model （q2=0.707, R2=0.964） and CoMSIA model （q2=0.645, R2=0.972）. The external validation indicated that both CoMFA and CoMSIA models were quite robust and had high predictive power with the predictive correlation coefficient values of 0.707 and 0.794, essen- 2 values of 0.792 and 0.826, the leave-one-out r2m（LOO） values of 0.781 and tim parameter rm2 0.809, r2（ all） values of 0.787 and 0.810, respectively. Moreover, the appropriate binding orientations and conformations of these compounds interacting with Wee1 were revealed by the docking studies. Based on the CoMFA and CoMSIA contour maps and docking analyses, several key structural requirements of these compounds responsible for inhibitory activity were identified as follows： simultaneously introducing high electropositive groups to the sub- stituents R1 and R5 may increase the activity, the substituent R2 should be smaller bulky and higher electronegative, moderate-size and strong electron-withdrawing groups for the substituent R3 is advantageous to the activity, but the substituent X should be medium-size and hydrophilic. These theoretical results help to understand the action mechanism and design novel potential Wee1 inhibitors.展开更多
文摘In order to investigate the inhibiting mechanism and obtain some helpful information for designing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies have been performed on 45 pyrido[2,3-d] pyrimidine derivatives acting as Wee1 inhibitors. Two optimal 3D-QSAR models with significant statistical quality and satisfactory predictive ability were established, including the CoMFA model （q2=0.707, R2=0.964） and CoMSIA model （q2=0.645, R2=0.972）. The external validation indicated that both CoMFA and CoMSIA models were quite robust and had high predictive power with the predictive correlation coefficient values of 0.707 and 0.794, essen- 2 values of 0.792 and 0.826, the leave-one-out r2m（LOO） values of 0.781 and tim parameter rm2 0.809, r2（ all） values of 0.787 and 0.810, respectively. Moreover, the appropriate binding orientations and conformations of these compounds interacting with Wee1 were revealed by the docking studies. Based on the CoMFA and CoMSIA contour maps and docking analyses, several key structural requirements of these compounds responsible for inhibitory activity were identified as follows： simultaneously introducing high electropositive groups to the sub- stituents R1 and R5 may increase the activity, the substituent R2 should be smaller bulky and higher electronegative, moderate-size and strong electron-withdrawing groups for the substituent R3 is advantageous to the activity, but the substituent X should be medium-size and hydrophilic. These theoretical results help to understand the action mechanism and design novel potential Wee1 inhibitors.
