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

Journal of Medicinal Chemistry
Daniel K NevinDavid G Lloyd

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 (EC(50) of 215 nM to 5.45 μM). Consequent characterization by a TR-FRET activation reporter assay demonstrated agonism of PPARγ by all three compounds (EC(50) of 467-594 nM). Additionally, diff...Continue Reading

References

Feb 4, 1998·The Journal of Steroid Biochemistry and Molecular Biology·T E JohnsonA Schmidt
Jan 23, 1999·Medical Decision Making : an International Journal of the Society for Medical Decision Making·D Mossman
Apr 29, 1999·Cell·UNKNOWN Nuclear Receptors Nomenclature Committee
Jun 6, 2000·Nature·S KerstenW Wahli
Oct 26, 2001·Bioorganic & Medicinal Chemistry Letters·K G LiuD D Sternbach
Jan 31, 2002·Annual Review of Medicine·Joel Berger, David E Moller
Apr 6, 2004·Korean Journal of Radiology : Official Journal of the Korean Radiological Society·Seong Ho ParkChan-Hee Jo
Nov 29, 2005·Journal of Chemical Information and Modeling·Andrew J S KnoxDavid G Lloyd
Feb 4, 2006·Current Pharmaceutical Design·Antonietta Bernardo, Luisa Minghetti
Feb 18, 2006·Journal of Neurology, Neurosurgery, and Psychiatry·R BordetJ-C Fruchart
Dec 13, 2006·Journal of Medicinal Chemistry·Niu HuangJohn J Irwin
Jun 27, 2007·Diabetes, Obesity & Metabolism·Alice Y Y Cheng, Lawrence A Leiter
Jul 3, 2007·Biochimica Et Biophysica Acta·Barry G Shearer, Andrew N Billin
Dec 14, 2007·Journal of Computer-aided Molecular Design·Ajay N Jain
Apr 4, 2008·Journal of Neurochemistry·Rajnish K Chaturvedi, M Flint Beal
Oct 7, 2008·Archivum Immunologiae Et Therapiae Experimentalis·Andrzej ZieleniakLucyna A Woźniak
Nov 15, 2008·Expert Opinion on Therapeutic Targets·John J BrightSharmistha Chakraborty
Jan 1, 2009·Proceedings of the National Academy of Sciences of the United States of America·Dean R ArtisJames F Tobin
Jul 23, 2009·Acta Crystallographica. Section D, Biological Crystallography·Takuji OyamaKosuke Morikawa
Mar 26, 2010·Journal of Medicinal Chemistry·Valeria OnnisDavid G Lloyd
Nov 26, 2010·Journal of Chemical Information and Modeling·Vishwesh VenkatramanDavid W Ritchie
Dec 17, 2011·Current Medicinal Chemistry·D K NevinD Fayne
May 31, 2012·Journal of Computer-aided Molecular Design·Wendy A Warr

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Citations

Mar 27, 2015·Journal of Molecular Recognition : JMR·Elizabeth YurievPaul A Ramsland
Sep 24, 2020·Journal of Biomolecular Structure & Dynamics·Shubhangi Kandwal, Darren Fayne
Sep 5, 2020·Journal of Medicinal Chemistry·Konstantin HinnahDirk Trauner

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