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Reliable structural information for rational design of benzoxazole type potential cholesteryl ester transfer protein (CETP) inhibitors through multiple validated modeling techniques.

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.

journal_name

J Biomol Struct Dyn

journal_title

Journal of biomolecular structure & dynamics

authors

Amin SA,Adhikari N,Gayen S,Jha T

doi

10.1080/07391102.2018.1552895

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

4528-4541

issue

eissn

0739-1102

issn

1538-0254

journal_volume

pub_type

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Reliable structural information for rational design of benzoxazole type potential cholesteryl ester transfer protein (CETP) inhibitors through multiple validated modeling techniques.