Guo-hua Zeng, Wen-juan Wu, Rong Zhang, Jun Sun, Wen-guo Xie, Yong Shen. 3D-QSAR and Docking Studies of Pyrido[2,3-d]pyrimidine Derivatives as Wee1 Inhibitors[J]. Chinese Journal of Chemical Physics , 2012, 25(3): 297-307. doi: 10.1088/1674-0068/25/03/297-307
Citation: Guo-hua Zeng, Wen-juan Wu, Rong Zhang, Jun Sun, Wen-guo Xie, Yong Shen. 3D-QSAR and Docking Studies of Pyrido[2,3-d]pyrimidine Derivatives as Wee1 Inhibitors[J]. Chinese Journal of Chemical Physics , 2012, 25(3): 297-307. doi: 10.1088/1674-0068/25/03/297-307

3D-QSAR and Docking Studies of Pyrido[2,3-d]pyrimidine Derivatives as Wee1 Inhibitors

doi: 10.1088/1674-0068/25/03/297-307
Funds:  This work was supported by the National Natu-ral Science Foundation of China (No.20903026), the Natural Science Foundation of Guangdong province (No.S2011010002483 and No.S2011010002964), the Sci-ence and Technology Planning Project of Guangdong Province
  • Received Date: 2011-12-21
  • In order to investigate the inhibiting mechanism and obtain some helpful information for de-signing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies have been performed on 45 pyrido[2,3-d] pyrim-idine 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 val-idation 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-tial parameter r2m values of 0.792 and 0.826, the leave-one-out r2m(LOO) values of 0.781 and 0.809, r2m(overall) 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.
  • 加载中
  • 加载中
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Article Metrics

Article views(2102) PDF downloads(1216) Cited by()

Proportional views
Related

3D-QSAR and Docking Studies of Pyrido[2,3-d]pyrimidine Derivatives as Wee1 Inhibitors

doi: 10.1088/1674-0068/25/03/297-307
Funds:  This work was supported by the National Natu-ral Science Foundation of China (No.20903026), the Natural Science Foundation of Guangdong province (No.S2011010002483 and No.S2011010002964), the Sci-ence and Technology Planning Project of Guangdong Province

Abstract: In order to investigate the inhibiting mechanism and obtain some helpful information for de-signing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies have been performed on 45 pyrido[2,3-d] pyrim-idine 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 val-idation 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-tial parameter r2m values of 0.792 and 0.826, the leave-one-out r2m(LOO) values of 0.781 and 0.809, r2m(overall) 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.

Guo-hua Zeng, Wen-juan Wu, Rong Zhang, Jun Sun, Wen-guo Xie, Yong Shen. 3D-QSAR and Docking Studies of Pyrido[2,3-d]pyrimidine Derivatives as Wee1 Inhibitors[J]. Chinese Journal of Chemical Physics , 2012, 25(3): 297-307. doi: 10.1088/1674-0068/25/03/297-307
Citation: Guo-hua Zeng, Wen-juan Wu, Rong Zhang, Jun Sun, Wen-guo Xie, Yong Shen. 3D-QSAR and Docking Studies of Pyrido[2,3-d]pyrimidine Derivatives as Wee1 Inhibitors[J]. Chinese Journal of Chemical Physics , 2012, 25(3): 297-307. doi: 10.1088/1674-0068/25/03/297-307

Catalog

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return