CoMFA, CoMSIA and eigenvalue analysis on dibenzodioxepinone and dibenzodioxocinone derivatives as cholesteryl ester transfer protein inhibitors.
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.
Xiong
Xu-qiong
XQ
Key Lab of New Drugs Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. marywind@gmail.com
Zhao
Dong-mei
DM
Bu
Peng-fei
PF
Liu
Yang
Y
Ren
Jin-hong
JH
Wang
Jian
J
Cheng
Mao-sheng
MS
D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010082:Oxepins / Q000737:chemistry / Q000494:pharmacology*; D035964:Oxocins / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D053480:Cholesterol Ester Transfer Proteins; D004791:Enzyme Inhibitors; D010082:Oxepins; D035964:Oxocins
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