Paper Report for: Abuhamdah_2013_J.Comput.Aided.Mol.Des_27_1075
Reference
Title: Elaborate ligand-based modeling coupled with QSAR analysis and in silico screening reveal new potent acetylcholinesterase inhibitors Abuhamdah S, Habash M, Taha MO Ref: J Comput Aided Mol Des, 27:1075, 2013 : PubMed
Inhibition of the enzyme acetylcholinesterase (AChE) has been shown to alleviate neurodegenerative diseases prompting several attempts to discover and optimize new AChE inhibitors. In this direction, we explored the pharmacophoric space of 85 AChE inhibitors to identify high quality pharmacophores. Subsequently, we implemented genetic algorithm-based quantitative structure-activity relationship (QSAR) modeling to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation among training compounds ([Formula: see text], F-statistic = 125.8, [Formula: see text], [Formula: see text] against 17 external test inhibitors = 0.84). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within AChE binding pocket. The successful pharmacophores were comparable with crystallographically resolved AChE binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute list of compounds. Twenty-four low micromolar AChE inhibitors were identified. The most potent gave IC50 value of 1.0 muM.
        
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Abuhamdah S, Habash M, Taha MO (2013) Elaborate ligand-based modeling coupled with QSAR analysis and in silico screening reveal new potent acetylcholinesterase inhibitors J Comput Aided Mol Des27: 1075-92
Abuhamdah S, Habash M, Taha MO (2013) J Comput Aided Mol Des27: 1075-92