Mechanisms
Multi-model computational study of 140 benzoxazole compounds maps the structural requirements for potent CETP inhibition (J Biomol Struct Dyn 2019)
Original title: Reliable structural information for rational design of benzoxazole type potential cholesteryl ester transfer protein (CETP) inhibitors through multiple validated modeling techniques
With no new lipid modulator reaching market in 35 years and the off-target toxicity of torcetrapib a cautionary example, this study applied pharmacophore mapping, molecular docking, 3D-QSAR comparative molecular field analysis (CoMFA), topomer CoMFA and Bayesian classification to 140 benzoxazole compounds to define the structural requirements for CETP inhibition. The best pharmacophore hypothesis was statistically strong (regression coefficient 0.957), and molecular docking showed cyano-substituted compounds form hydrogen bonds with CETP. The 3D-QSAR CoMFA model reached a cross-validated Q2 of 0.527 and R-squared of 0.853, with two topomer CoMFA models also statistically reliable, and Bayesian classification achieved ROC values of 0.919 and 0.939 for training and test sets. The authors present this as a framework to guide rational design of new benzoxazole-type CETP inhibitors, an entirely computational study with no synthesis or biological testing.
Original abstract
The drug design and discovery of lipid modulators is very demanding as no new molecule has entered into the market in the last 35 years. Cholesteryl ester transfer protein (CETP) is a promising target as lipid modulators. Inhibition of the CETP enzyme reduces the risk of cardiovascular events. The first CETP inhibitor torcetrapib and related drug candidates failed in the clinical trial due to the off-target effects leading to high toxicity. Thus, newer CETP inhibitors have now paramount importance to accelerate the drug discovery efforts in the field of cardiovascular disease (CVD). In the present study, 140 benzoxazole compounds were studied by using different chemometric techniques, for example, pharmacophore mapping, molecular docking, three-dimensional quantitative structure-activity relationship comparative molecular field analysis (3D-QSAR CoMFA), topomer CoMFA and Bayesian classification, in order to generate complete and reliable information regarding the structural requirements for the CETP inhibition. The best pharmacophore hypothesis was statistically significant (regression coefficient of 0.957 and a lower root mean square of 0.890). Molecular docking study revealed that cyano-substituted compounds form hydrogen bond with targeted macromolecule. The 3D-QSAR CoMFA model also produced a leave-one-out (LOO) cross-validated Q2 of 0.527, an R2 of 0.853 and an R2Pred of 0.603. Similarly, two topomer CoMFA models were also statistically significant and reliable in terms of their Q2, R2 and R2Pred values. The Bayesian classification study also provided the excellent ROC values of 0.919 and 0.939 for training and test sets, respectively. Overall, this study may help in the rational design of newer benzoxazole type compounds with higher CETP inhibition. Communicated by Ramaswamy H. Sarma.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.