6533b7dbfe1ef96bd12715cc

RESEARCH PRODUCT

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

David LloydDarren FayneLaura CaboniFernando BlancoJaime Rubio-martinezMaria Galvez-llompartJorge Galvez

subject

StereochemistryGeneral Chemical EngineeringMolecular ConformationLibrary and Information SciencesMolecular Dynamics Simulationmolecular topologySmall Molecule LibrariesMolecular dynamicschemistry.chemical_compoundStructure-Activity RelationshipUser-Computer Interfaceexperimental validationDrug DiscoveryFluorescence Resonance Energy TransferMoleculeHumansPyrrolesPyrroleBinding SitesChemistryAntagonistAndrogen AntagonistsGeneral Chemistryvirtual screeningComputer Science ApplicationsHigh-Throughput Screening AssaysAndrogen receptorMolecular Docking SimulationFörster resonance energy transferDocking (molecular)Receptors AndrogenThermodynamicsFluorescence anisotropyProtein Binding

description

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. Refereed/Peer-reviewed

yearjournalcountryeditionlanguage
2014-09-19
10.1021/ci500324fhttps://hdl.handle.net/1959.8/162500