Integrated virtual screening for the identification of novel and selective peroxisome proliferator-activated receptor (PPAR) scaffolds.

Article Details

Citation

Copy to clipboard

Nevin DK, Peters MB, Carta G, Fayne D, Lloyd DG

Integrated virtual screening for the identification of novel and selective peroxisome proliferator-activated receptor (PPAR) scaffolds.

J Med Chem. 2012 Jun 14;55(11):4978-89. doi: 10.1021/jm300068n. Epub 2012 May 24.

PubMed ID

22582973 [ View in PubMed

]

Abstract

We describe a fully customizable and integrated target-specific "tiered" virtual screening approach tailored to identifying and characterizing novel peroxisome proliferator activated receptor gamma (PPARgamma) 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 PPARgamma. 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-pyrr ol-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 PPARgamma-LBD (EC(50) of 215 nM to 5.45 muM). Consequent characterization by a TR-FRET activation reporter assay demonstrated agonism of PPARgamma by all three compounds (EC(50) of 467-594 nM). Additionally, differential PPAR isotype specificity was demonstrated through assay against PPARalpha and PPARdelta 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	120	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	190	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	2.4	N/A	N/A	Details