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

International Journal of Molecular Sciences - Tập 15 Số 5 - Trang 7651-7666
Ivanka Tsakovska1, Merilin Al Sharif1, Petko Alov1, Antonia Diukendjieva1, Elena Fioravanzo2, Mark T.D. Cronin3, Ilza Pajeva1
1Institute of Biophysics and Biomedical Engineering—BAS, Acad. G. Bonchev Str., Bl.105, Sofia 1113, Bulgaria
2Soluzioni Informatiche srl, Via Ferrari 14, Vicenza 36100, Italy
3School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK

Tóm tắt

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.

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Tài liệu tham khảo

Gocht, 2012, Mode of action working group: Use of mode of action related to repeated dose systemic toxicity—A framework for capturing Information, Towards the Replacement of in Vivo Repeated Dose Systemic Toxicity Testing, 2, 284

(2013). Series on Testing and Assessment No. 184, OECD.

Fioravanzo, 2013, Molecular modelling of LXR binding to evaluate the potential for liver steatosis, Toxicol. Lett, 221, S83, 10.1016/j.toxlet.2013.05.092

Alov, 2013, Toward better understanding of liver steatosis MoA: Molecular modelling study of PPAR gamma receptor, Toxicol. Lett, 221, S85, 10.1016/j.toxlet.2013.05.099

Alov, 2014, Modes-of-action related to repeated dose toxicity: Tissue-specific biological roles of PPARγ ligand-dependent dysregulation in nonalcoholic fatty liver disease, PPAR Res, 2014, 432647:1

Landesmann, B., Goumenou, M., Munn, S., and Whelan, M. Description of Prototype Modes-Of-Action Related to Repeated dose Toxicity. 40 Pages, EUR 25631 EN. Available online: http://publications.jrc.ec.europa.eu.

Costa, 2010, PPARG: Gene expression regulation and next-generation sequencing for unsolved issues, PPAR Res, 2010, 409168:1, 10.1155/2010/409168

Kouskoumvekaki, 2013, Discovery of a Novel Selective PPARγ Ligand with Partial Agonist Binding Properties by Integrated in Silico/in Vitro Work Flow, J. Chem. Inf. Model, 53, 923, 10.1021/ci3006148

Day, 1999, Thiazolidinediones: A new class of antidiabetic drugs, Diabet. Med, 16, 179, 10.1046/j.1464-5491.1999.00023.x

Moya, 2010, Enhanced steatosis by nuclear receptor ligands: A study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile, Chem. Biol. Interact, 184, 376, 10.1016/j.cbi.2010.01.008

Pan, 2006, Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: Relation to dysregulated phosphatidylcholine metabolism, Vascul. Pharmacol, 45, 65, 10.1016/j.vph.2005.11.011

Bruning, 2007, Partial agonists activate PPARgamma using a helix 12 independent mechanism, Structure, 15, 1258, 10.1016/j.str.2007.07.014

Guasch, 2012, Identification of PPARgamma partial agonists of natural origin (I): Development of a virtual screening procedure and in vitro validation, PLoS One, 7, e50816, 10.1371/journal.pone.0050816

Berman, 2000, The protein data bank, Nucleic Acids Res, 28, 235, 10.1093/nar/28.1.235

Waku, 2010, The nuclear receptor PPARγ individually responds to serotonin- and fatty acid- metabolites, EMBO J, 29, 3395, 10.1038/emboj.2010.197

Itoh, 2008, Structural basis for the activation of PPARγ by oxidized fatty acids, Nat. Struct. Mol. Biol, 15, 924, 10.1038/nsmb.1474

Li, 2008, Molecular recognition of nitrated fatty acids by PPARγ, Nat. Struct. Mol. Biol, 15, 865, 10.1038/nsmb.1447

Gampe, 2000, Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors, Mol Cell, 5, 545, 10.1016/S1097-2765(00)80448-7

Liberato, 2012, Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR)γ activators and pan-PPAR partial agonists, PLoS One, 7, e36297, 10.1371/journal.pone.0036297

Chandra, 2008, Structure of the intact PPAR-γ-RXR-nuclear receptor complex on DNA, Nature, 456, 350, 10.1038/nature07413

Nolte, 1998, Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma, Nature, 395, 137, 10.1038/25931

Li, 2008, Structural and biochemical basis for the binding selectivity of peroxisome proliferator-activated receptor gamma to PGC-1α, J. Biol. Chem, 283, 19132, 10.1074/jbc.M802040200

Li, 2005, Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner, Proc. Natl. Acad. Sci. USA, 102, 9505, 10.1073/pnas.0501204102

Pencheva, 2012, Post-docking optimization and analysis of protein-ligand interactions of estrogen receptor alpha using ammos software, Curr. Comput. Aided Drug Des, 9, 83, 10.2174/1573409911309010008

Xu, 2001, Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors, Proc. Natl. Acad. Sci. USA, 98, 13919, 10.1073/pnas.241410198

Ohashi, 2011, Design, synthesis, and structural analysis of phenylpropanoic acid-type PPARγ-selective agonists: Discovery of reversed stereochemistry-activity relationship, J. Med. Chem, 54, 331, 10.1021/jm101233f

Zhang, 2009, Design, synthesis and structure-activity relationships of azole acids as novel, potent dual PPAR alpha/gamma agonists, Bioorg. Med. Chem. Lett, 19, 1451, 10.1016/j.bmcl.2009.01.030

Bigge, 2009, Synthesis and evaluation of novel α-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists, Bioorg. Med Chem, 17, 7113, 10.1016/j.bmc.2009.09.001

Cronet, 2001, Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family, Structure, 9, 699, 10.1016/S0969-2126(01)00634-7

Benz, 2009, Aleglitazar, a new, potent, and balanced dual PPARα/γ agonist for the treatment of type II diabetes, Bioorg. Med. Chem. Lett, 19, 2468, 10.1016/j.bmcl.2009.03.036

Oyama, 2009, Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures, Acta. Crystallogr. D Biol. Crystallogr, 65, 786, 10.1107/S0907444909015935

Lin, 2009, Design an d structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists, J. Med. Chem, 52, 2618, 10.1021/jm801594x

Kuwabara, 2012, 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, J. Med. Chem, 55, 893, 10.1021/jm2014293

Mahindroo, 2006, Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: Design, synthesis, structural biology, and molecular docking studies, J. Med. Chem, 49, 1212, 10.1021/jm0510373

Bigge, 2008, Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARα/γ dual agonists, and X-ray crystallographic studies, Bioorg. Med. Chem, 16, 4883, 10.1016/j.bmc.2008.03.043

Sauerberg, 2002, Novel tricyclic-alpha-alkyloxyphenylpropionic acids: Dual PPARα/γ agonists with hypolipidemic and antidiabetic activity, J. Med. Chem, 45, 789, 10.1021/jm010964g

Grether, 2009, Design and biological evaluation of novel, balanced dual PPARα/γ agonists, ChemMedChem, 4, 951, 10.1002/cmdc.200800425

Mahindroo, 2006, Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor agonists, J. Med. Chem, 49, 6421, 10.1021/jm060663c

Mahindroo, 2005, Novel indole-based peroxisome proliferator-activated receptor agonists: Design, SAR, structural biology, and biological activities, J. Med. Chem, 48, 8194, 10.1021/jm0506930

Mueller, J.J., Schupp, M., Unger, T., Kintscher, U., and Heinemann, U. (2011). Binding Diversity of Pioglitazone by Peroxisome Proliferator-Activated Receptor-Gamma, Unpublished work.

Ebdrup, 2003, Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar, J. Med. Chem, 46, 1306, 10.1021/jm021027r

Kuhn, 2006, Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists, Bioorg. Med. Chem. Lett, 16, 4016, 10.1016/j.bmcl.2006.05.007

(2013). MOE (Molecular Operating Environment) Version 2013.08, Chemical Computing Group Inc.

Gaulton, 2012, ChEMBL: A large-scale bioactivity database for drug discovery, Nucleic Acids Res, 40, D1100, 10.1093/nar/gkr777