کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1399591 | 1501190 | 2010 | 20 صفحه PDF | دانلود رایگان |
Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein particles and neutral lipids between HDL and LDL and therefore is considered a valid target for treating dyslipidemic conditions and complications. Pharmacophore modeling and quantitative structure–activity relationship (QSAR) analysis were combined to explore the structural requirments for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r2 = 0.800, n = 96, F = 72.1, r2LOO = 0.775, r2PRESS against 22 external test inhibitors = 0.707) suggesting the existence of at least two distinct binding modes accessible to ligands within CETP binding pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles.The validity of our modeling approach was experimentally established by the identification of several CETP inhibitory leads retrieved via in silico screening of the National Cancer Institute (NCI) list of compounds and an in house built database of drugs and agrochemicals. Two hits illustrated low micromolar IC50 values: NSC 40331 (IC50 = 6.5 μM) and NSC 89508 (IC50 = 1.9 μM). Active hits were then used to guide synthetic exploration of a new series of CETP inhibitors.
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Journal: European Journal of Medicinal Chemistry - Volume 45, Issue 4, April 2010, Pages 1598–1617