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Title:Integrated Virtual Screening for the Identification of Novel and Selective Peroxisome Proliferator-Activated Receptor (PPAR) Scaffolds
Authors:Daniel K. Nevin, Martin B. Peters, Giorgio Carta, Darren Fayne, and David G. Lloyd, 2012
Abstract: We describe a fully customizable and integrated target-specific “tiered” virtual screening approach tailored to identifying and characterizing novel peroxisome proliferator activated receptor γ (PPARγ) scaffolds. Built on structure- and ligand-based computational techniques, a consensus protocol was developed for use in the virtual screening of chemical databases, focused toward retrieval of novel bioactive chemical scaffolds for PPARγ. Consequent from application, three novel PPAR scaffolds displaying distinct chemotypes have been identified, namely, 5-(4-(benzyloxy)-3-chlorobenzylidene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione (MDG 548), 3-((4-bromophenoxy)methyl)-N-(4-nitro-1H-pyrazol-1-yl)benzamide (MDG 559), and ethyl 2-[3-hydroxy-5-(5-methyl-2-furyl)-2-oxo-4-(2-thienylcarbonyl)-2,5-dihydro-1H-pyrrol-1-yl]-4-methyl-1,3-thiazole-5-carboxylate (MDG 582). Fluorescence polarization(FP) and time resolved fluorescence resonance energy transfer (TR-FRET) show that these compounds display high affinity competitive binding to the PPARγ-LBD (EC50 of 215 nM to 5.45 μM). Consequent characterization by a TR-FRET activation reporter assay demonstrated agonism of PPARγ by all three compounds (EC50 of 467–594nM). Additionally, differential PPAR isotype specificity was demonstrated through assay against PPARα and PPARδ subtypes. This work showcases the ability of target specific “tiered screen” protocols to successfully identify novel scaffolds of individual receptor subtypes with greater efficacy than isolated screening methods.
ICHEC Project:PPARgamma Tiered Virtual Screening- Development of an Improved Post-Hit Scoring Process
Publication:J. Med. Chem., Article ASAP, May 14, 2012
URL: http://pubs.acs.org/doi/abs/10.1021/jm300068n
Keywords: Virtual Screening;drug discovery;workflows
Status: Published

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