CoMFA, CoMSIA and Eigenvalue Analysis on Dibenzodioxepinone and Dibenzodioxocinone Derivatives as Cholesteryl Ester Transfer Protein Inhibitors

Molecules

Xu-qiong Xiong¹  Dong-mei Zhao¹  Peng-fei Bu¹  Yang Liu¹  Jin-hong Ren¹  Jian Wang¹ 

[1] Key Lab of New Drugs Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; E-mails

关键词: CoMFA;    CoMSIA;    eigenvalue analysis;    dibenzodioxepinone and dibenzodioxocinone analogues;    cholesteryl ester transfer protein inhibitors;   

DOI  :  10.3390/molecules13081822

来源: mdpi

【 摘 要 】

CoMFA, CoMSIA and eigenvalue analysis (EVA) were performed to study the structural features of 61 diverse dibenzodioxepinone and dibenzodioxocinone analogues to probe cholesteryl ester transfer protein (CETP) inhibitory activity. Three methods yielded statistically significant models upon assessment of cross-validation, bootstrapping, and progressive scrambling. This was further validated by an external set of 13 derivatives. Our results demonstrate that three models have a good interpolation as well as extrapolation. The hydrophobic features were confirmed to contribute significantly to inhibitor potencies, while a pre-oriented hydrogen bond provided by the hydroxyl group at the 3-position indicated a good correlation with previous SAR, and a hydrogen bond acceptor may play a crucial role in CETP inhibition. These derived models may help us to gain a deeper understanding of the binding interaction of these lactone-based compounds and aid in the design of new potent compounds against CETP.

【 授权许可】

CC BY   
© 2008 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.