title: Rational screening of peroxisome proliferator-activated receptor-γ agonists from natural products: potential therapeutics for heart failure.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Activation of PPARγ pathway has been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis in heart failure. Thus, the protein has been raised as an attractive target for heart failure therapy.
  
  
  OBJECTIVE
  This work attempted to discover new and potent PPARγ agonists from natural products using a synthetic strategy of computer virtual screening and transactivation reporter assay.
  
  
  METHODS
  A large library of structurally diverse, drug-like natural products was compiled, from which those with unsatisfactory pharmacokinetic profile and/or structurally redundant compounds were excluded. The binding mode of remaining candidates to PPARγ ligand-binding domain (LBD) was computationally modelled using molecular docking and their relative binding potency was ranked by an empirical scoring scheme. Consequently, eight commercially available hits with top scores were selected and their biological activity was determined using a cell-based reporter-gene assay.
  
  
  RESULTS
  Four natural product compounds, namely ZINC13408172, ZINC4292805, ZINC44179 and ZINC901461, were identified to have high or moderate agonistic potency against human PPARγ with EC50values of 0.084, 2.1, 0.35 and 5.6 μM, respectively, which are comparable to or even better than that of the approved PPARγ full agonists pioglitazone (EC50=0.16 μM) and rosiglitazone (EC50=0.034 μM). Hydrophobic interactions and van der Waals contacts are the primary chemical forces to stabilize the complex architecture of PPARγ LBD domain with these agonist ligands, while few hydrogen bonds, salt bridges and/or π-π stacking at the complex interfaces confer selectivity and specificity for the domain-agonist recognition.
  
  
  CONCLUSIONS
  The integrated in vitro-in silico screening strategy can be successfully applied to rational discovery of biologically active compounds. The newly identified natural products with PPARγ agonistic potency are considered as promising lead scaffolds to develop novel chemical therapeutics for heart failure.
authors.affiliation: a Department of Geriatric Medicine , Shanghai Eighth People's Hospital , Shanghai , China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: a Department of Geriatric Medicine , Shanghai Eighth People's Hospital , Shanghai , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wan
authors.affiliation: a Department of Geriatric Medicine , Shanghai Eighth People's Hospital , Shanghai , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Song
authors.affiliation: a Department of Geriatric Medicine , Shanghai Eighth People's Hospital , Shanghai , China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: a Department of Geriatric Medicine , Shanghai Eighth People's Hospital , Shanghai , China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: b Department of Cardiology , Shanghai Eighth People's Hospital , Shanghai , China.
authors.forename: Shuiming
authors.initials: S
authors.lastname: Gu
mesh_terms: D000818:Animals; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002317:Cardiovascular Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D017930:Genes, Reporter; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D001688:Biological Products; D002317:Cardiovascular Agents; D008024:Ligands; D047495:PPAR gamma
keywords: Natural medicine discovery; brain natriuretie peptide; protein-ligand recognition; virtual screening