Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration

European Journal of Medicinal Chemistry
Reema Abu KhalafMutasem O Taha

Abstract

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 requirements for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r(2)=0.800, n=96, F=72.1, r(2)(LOO) =0.775, r(2)(PRESS) 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 IC(50) values: NSC 40331 (IC(50)=6.5 microM) and NSC 89508 (IC(50)=1.9 microM). Active hits were then u...Continue Reading

Citations

Dec 15, 2011·Journal of Computer-aided Molecular Design·Rand ShahinMutasem O Taha
Apr 23, 2013·Journal of Molecular Graphics & Modelling·Mahmoud A Al-Sha'erMutasem O Taha
Dec 18, 2013·Journal of Computer-aided Molecular Design·Sawsan AbuhamdahMutasem O Taha
May 23, 2012·Journal of Molecular Graphics & Modelling·Ghadeer A R Y SuaifanMutasem O Taha
Mar 10, 2016·Chemico-biological Interactions·Nour H AboalhaijaMutasem O Taha
Aug 24, 2010·Journal of Computational Chemistry·Ahmed Mutanabbi AbdulaMutasem O Taha
Apr 13, 2011·European Journal of Medicinal Chemistry·Belal O Al-NajjarMutasem O Taha
Jan 13, 2015·Journal of Molecular Graphics & Modelling·Mutasem O TahaAmjad Qandil
Aug 21, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ghassan Abu SheikhaGhadeer Albadawi
Feb 8, 2019·Anti-cancer Agents in Medicinal Chemistry·Magda M F IsmailMarwa F Harras
Dec 12, 2018·Current Computer-aided Drug Design·Reema A KhalafDima Sabbah
Sep 14, 2010·Journal of Chemical Information and Modeling·Mahmoud A Al-Sha'er, Mutasem O Taha

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