Pharmacophore modeling, quantitative structure-activity relationship analysis, and in silico screening reveal potent glycogen synthase kinase-3beta inhibitory activities for cimetidine, hydroxychloroquine, and gemifloxacin.

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Taha MO, Bustanji Y, Al-Ghussein MA, Mohammad M, Zalloum H, Al-Masri IM, Atallah N

J Med Chem. 2008 Apr 10;51(7):2062-77. doi: 10.1021/jm7009765. Epub 2008 Mar 7.

PubMed ID

18324764 [ View in PubMed

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Abstract

The pharmacophoric space of glycogen synthase kinase-3beta (GSK-3beta) was explored using two diverse sets of inhibitors. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophores and physicochemical descriptors that access self-consistent and predictive quantitative structure-activity relationship (QSAR) against 132 training compounds ( r (2) 123 = 0.663, F = 24.6, r (2) LOO = 0.592, r (2) PRESS against 29 external test inhibitors = 0.695). Two orthogonal pharmacophores emerged in the QSAR, suggesting the existence of at least two distinct binding modes accessible to ligands within GSK-3beta binding pocket. The validity of the QSAR equation and the associated pharmacophores was established by the identification of three nanomolar GSK-3beta inhibitors retrieved from our in-house-built structural database of established drugs, namely, hydroxychloroquine, cimetidine, and gemifloxacin. Docking studies supported the binding modes suggested by the pharmacophore/QSAR analysis. In addition to being excellent leads for subsequent optimization, the anti-GSK-3beta activities of these drugs should have significant clinical implications.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
SB-409513	Glycogen synthase kinase-3 beta	IC 50 (nM)	76	N/A	N/A	Details