title: 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.
abstract: 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-activity 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.
authors.affiliation: Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Laura
authors.initials: L
authors.lastname: Caboni
authors.forename: Maria
authors.initials: M
authors.lastname: Gálvez-Llompart
authors.forename: Jorge
authors.initials: J
authors.lastname: Gálvez
authors.forename: Fernando
authors.initials: F
authors.lastname: Blanco
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
authors.forename: Darren
authors.initials: D
authors.lastname: Fayne
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry*; D001665:Binding Sites; D055808:Drug Discovery; D031541:Fluorescence Resonance Energy Transfer; D057166:High-Throughput Screening Assays; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry*; D011944:Receptors, Androgen / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D011758:Pyrroles; D011944:Receptors, Androgen; D054852:Small Molecule Libraries