Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

The comprehensive understanding of the precise mode of action and/or adverse outcome pathway (MoA/AOP) of chemicals has become a key step toward the development of a new generation of predictive toxicology tools. One of the challenges of this process is to test the feasibility of the molecular modelling approaches to explore key molecular initiating events (MIE) within the integrated strategy of MoA/AOP characterisation. The description of MoAs leading to toxicity and liver damage has been the focus of much interest. Growing evidence underlines liver PPARγ ligand-dependent activation as a key MIE in the elicitation of liver steatosis. Synthetic PPARγ full agonists are of special concern, since they may trigger a number of adverse effects not observed with partial agonists. In this study, molecular modelling was performed based on the PPARγ complexes with full agonists extracted from the Protein Data Bank. The receptor binding pocket was analysed, and the specific ligand-receptor interactions were identified for the most active ligands. A pharmacophore model was derived, and the most important pharmacophore features were outlined and characterised in relation to their specific role for PPARγ activation. The results are useful for the characterisation of the chemical space of PPARγ full agonists and could facilitate the development of preliminary filtering rules for the effective virtual ligand screening of compounds with PPARγ full agonistic activity.

[1]  Y. E. Chen,et al.  Molecular recognition of nitrated fatty acids by PPARγ , 2008, Nature Structural &Molecular Biology.

[2]  Shuichi Hirono,et al.  Design, synthesis, and structural analysis of phenylpropanoic acid-type PPARγ-selective agonists: discovery of reversed stereochemistry-activity relationship. , 2011, Journal of medicinal chemistry.

[3]  Yong Li,et al.  Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  B. Kuhn,et al.  Aleglitazar, a new, potent, and balanced dual PPARalpha/gamma agonist for the treatment of type II diabetes. , 2009, Bioorganic & medicinal chemistry letters.

[5]  I-Lin Lu,et al.  Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities. , 2005, Journal of medicinal chemistry.

[6]  Naoyuki Kuwabara,et al.  Peroxisome proliferator-activated receptors (PPARs) have multiple binding points that accommodate ligands in various conformations: phenylpropanoic acid-type PPAR ligands bind to PPAR in different conformations, depending on the subtype. , 2012, Journal of medicinal chemistry.

[7]  P. Mohr.  Aleglitazar (I), a New, Potent, and Balanced Dual PPARα/γ Agonist for the Treatment of Type II Diabetes. , 2009 .

[8]  John P. Overington,et al.  ChEMBL: a large-scale bioactivity database for drug discovery , 2011, Nucleic Acids Res..

[9]  Andrew P. Worth,et al.  Molecular modelling of LXR binding to evaluate the potential for liver steatosis , 2013 .

[10]  N. Blomberg,et al.  Structure of the PPARα and -γ Ligand Binding Domain in Complex with AZ 242; Ligand Selectivity and Agonist Activation in the PPAR Family , 2001 .

[11]  Mohane Selvaraj Coumar,et al.  Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists. , 2009, Journal of medicinal chemistry.

[12]  Yoshitomo Hamuro,et al.  Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA , 2008, Nature.

[13]  Armin Ruf,et al.  Design and Biological Evaluation of Novel, Balanced Dual PPARα/γ Agonists , 2009, ChemMedChem.

[14]  Hairong Zhou,et al.  Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARalpha/gamma dual agonists, and X-ray crystallographic studies. , 2008, Bioorganic & medicinal chemistry.

[15]  Hans Peter Märki,et al.  Structure-based design of indole propionic acids as novel PPARα/γ co-agonists , 2006 .

[16]  J. Schwabe,et al.  Structural basis for the activation of PPARγ by oxidized fatty acids , 2008, Nature Structural &Molecular Biology.

[17]  Leandro Martínez,et al.  Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) γ Activators and Pan-PPAR Partial Agonists , 2012, PloS one.

[18]  J. Ohren,et al.  Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists. , 2009, Bioorganic & medicinal chemistry.

[19]  Y. Hashimoto,et al.  Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures , 2009, Acta crystallographica. Section D, Biological crystallography.

[20]  Ping-Chiang Lyu,et al.  Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: design, synthesis, structural biology, and molecular docking studies. , 2006, Journal of medicinal chemistry.

[21]  C. Day.  Thiazolidinediones: a new class of antidiabetic drugs , 1999, Diabetic medicine : a journal of the British Diabetic Association.

[22]  J. Castell,et al.  Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile. , 2010, Chemico-biological interactions.

[23]  Millard H. Lambert,et al.  Asymmetry in the PPARγ/RXRα Crystal Structure Reveals the Molecular Basis of Heterodimerization among Nuclear Receptors , 2000 .

[24]  Scott A. Busby,et al.  Partial agonists activate PPARgamma using a helix 12 independent mechanism. , 2007, Structure.

[25]  Petko Alov,et al.  Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease , 2014, PPAR research.

[26]  A. Ciccodicola,et al.  PPARG: Gene Expression Regulation and Next-Generation Sequencing for Unsolved Issues , 2010, PPAR research.

[27]  Tudor I. Oprea,et al.  Discovery of a Novel Selective PPARγ Ligand with Partial Agonist Binding Properties by Integrated in Silico/in Vitro Work Flow , 2013, J. Chem. Inf. Model..

[28]  Ingrid Pettersson,et al.  Novel Tricyclic-α-alkyloxyphenylpropionic Acids: Dual PPARα/γ Agonists with Hypolipidemic and Antidiabetic Activity , 2002 .

[29]  H. Xu,et al.  Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor γ to PGC-1α* , 2008, Journal of Biological Chemistry.

[30]  J. Fleckner,et al.  Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar. , 2003, Journal of medicinal chemistry.

[31]  Wei Wang,et al.  Design, synthesis and structure-activity relationships of azole acids as novel, potent dual PPAR alpha/gamma agonists. , 2009, Bioorganic & medicinal chemistry letters.

[32]  Munn Sharon,et al.  Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity , 2012 .

[33]  T. Willson,et al.  Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. , 2000, Molecular cell.

[34]  B. Kuhn,et al.  Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists. , 2006, Bioorganic & Medicinal Chemistry Letters.

[35]  J. Schwabe,et al.  Structural Basis for the Activation of Pparg by Oxidised Fatty Acids , 2008 .

[36]  Ping-Chiang Lyu,et al.  Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor agonists. , 2007, Journal of medicinal chemistry.

[37]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[38]  K. Morikawa,et al.  The nuclear receptor PPARγ individually responds to serotonin‐ and fatty acid‐metabolites , 2010, The EMBO journal.

[39]  Klaus R. Liedl,et al.  Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation , 2012, PloS one.

[40]  L. Moore,et al.  Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Vance,et al.  Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: relation to dysregulated phosphatidylcholine metabolism. , 2006, Vascular pharmacology.

[42]  N. Blomberg,et al.  Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. , 2001, Structure.