Molecular Topology Applied to the Discovery of 1-Benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a Non-Ligand-Binding-Pocket Antiandrogen

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• 作者：Laura Caboni ; Maria G谩lvez-Llompart ; Jorge G谩lvez ; Fernando Blanco ; Jaime Rubio-Martinez ; Darren Fayne ; David G. Lloyd
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2014
• 出版时间：October 27, 2014
• 年：2014
• 卷：54
• 期：10
• 页码：2953-2966
• 全文大小：551K
• ISSN：1549-960X

文摘

We report the discovery of 1-benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a novel non-ligand binding pocket (non-LBP) antagonist of the androgen receptor (AR) through the application of molecular topology techniques. This compound, validated through time-resolved fluorescence resonance energy transfer and fluorescence polarization biological assays, provides the basis for lead optimization and structure鈥揳ctivity relationship analysis of a new series of non-LBP AR antagonists. Induced-fit docking and molecular dynamics studies have been performed to establish a consistent hypothesis for the interaction of the new active molecule on the AR surface.