3D-QSAR study of 20 (S)-camptothecin analogs

Authors: LU, Ai-jun; ZHANG, Zhen-shan; ZHENG, Ming-yue; ZOU, Han-jun; LUO, Xiao-min; JIANG, Hua-liang

Source: Acta Pharmacologica Sinica, Volume 28, Number 2, February 2007 , pp. 307-314(8)

Buy & download fulltext article:

Price: $48.00 plus tax (Refund Policy)

Abstract:

Aim: 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 q²was 0.495. Then, the analysis of the non-cross-validated PLS model in which r²was 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. Conclusion: 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.

Keywords: comparative molecular field analysis (CoMFA); camptothecin (CPT); topoisomerase I (Top I)

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1745-7254.2007.00477.x

Affiliations: 1: Drug Discovery and Design Center, State Key Lab of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Publication date: 2007-02-01