3D-QSAR study of 20 (S)-camptothecin analogs.
OBJECTIVE
To build up a quantitative structure-activity relationship (QSAR) model of 20 (S)-camptothecin (CPT) analogs for the prediction of the activity of new CPT analogs for drug design.


METHODS
A training set of 43 structurally diverse CPT analogs which were inhibitors of topoisomerase I were used to construct a quantitative structure-activity relationship model with a comparative molecular field analysis (CoMFA). The QSAR model was optimized using partial least squares (PLS) analysis. A test set of 10 compounds was evaluated using the model.


RESULTS
The CoMFA model was constructed successfully, and a good cross-validated correlation was obtained in which q(2) was 0.495. Then, the analysis of the non-cross-validated PLS model in which r(2) was 0.935 was built and permitted demonstrations of high predictability for the activities of the 10 CPT analogs in the test set selected in random.


CONCLUSIONS
The CoMFA model indicated that bulky negative-charged group at position 9, 10 and 11 of CPT would increase activity, but excessively increasing bulky group at position 10 is adverse to inhibitory activity; substituents that occupy position 7 with the bulky positive group will enhance the inhibitive activity. The model can be used to design new CPT analogs and understand the mechanism of action.
Lu
Ai-jun
AJ
Jiangsu Simcere Pharmaceutical Research Company Ltd, Nanjing 210042, China.
Zhang
Zhen-shan
ZS
Zheng
Ming-yue
MY
Zou
Han-jun
HJ
Luo
Xiao-min
XM
Jiang
Hua-liang
HL
D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry*; D016018:Least-Squares Analysis; D021281:Quantitative Structure-Activity Relationship
D002166:Camptothecin