3D-QSAR Analysis on ATR Protein Kinase Inhibitors Using CoMFA and CoMSIA

作者：Li Xiurong; Shu Mao^*; Wang Yuanqiang; Yu Rui; Yao Shuang; Lin Zhihua

来源：Current Computer-Aided Drug Design, 2014, 10(4): 327-334.

• ATR inhibitor
• 3D-QSAR
• CoMFA
• CoMSIA
• docking
• homology modeling
• molecular design

Ataxia telangiectasia-mutated and Rad3-related (ATR) protein kinase is an attractive anticancer target. In this study, comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were performed on a series of aminopyrazine ATR inhibitors. The models generated by CoMFA had a cross-validated coefficient (q(2)) of 0.752 and a regression coefficient (r(2)) of 0.947. The CoMSIA models had a q(2) of 0.728 and an r(2) of 0.936. The reasonable quantitative structure-activity relationship model showed robust predictive ability. The contour map provided guidelines for building novel virtual compounds based on compound NO. 40. In addition, the 3D structure of ATR was modeled by homology modeling. Molecular dynamic simulations were employed to optimize the structure. The docking results offered insights into the interactions between the inhibitors and the active site for potent analysis. This study provides useful guidance for the discovery of more potent compounds.

• 出版日期2014
• 单位重庆理工大学; 重庆大学