The application of molecular modelling in the safety assessment of chemicals: A case study on ligand-dependent PPARγ dysregulation

Toxicology - Tập 392 - Trang 140-154 - 2017
Merilin Al Sharif1, Ivanka Tsakovska1, Ilza Pajeva1, Petko Alov1, Elena Fioravanzo2, Arianna Bassan2, Simona Kovarich2, Chihae Yang3, Aleksandra Mostrąg3, Vessela Vitcheva3,4, Andrew Worth5, A.-N. Richarz6, Mark T.D. Cronin6
1Institute of Biophysics and Biomedical Engineering—Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 105, 1113 Sofia, Bulgaria
2S-IN Soluzioni Informatiche SRL, Via Ferrari 14, Vicenza 36100, Italy
3Altamira LLC, 1455 Candlewood Drive, Columbus, OH 43235, USA
4Faculty of Pharmacy, Medical University of Sofia, "Dunav" 2 str., Sofia, Bulgaria
5Systems Toxicology Unit, Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra, Varese, Italy
6School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, England

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ACD/Labs Percepta suite, 2015. Advanced Chemistry Development, Inc. http://www.acdlabs.com/products/percepta/.

Acton, 2005, Benzoyl 2-methyl indoles as selective PPARγ modulators, Bioorg. Med. Chem. Lett., 15, 357, 10.1016/j.bmcl.2004.10.068

Adverse Outcome Pathway Knowledge Base (AOP-KB), 2015. https://aopkb.org/ (accessed July, 2015).

Al Sharif, 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, 1, 10.1155/2014/432647

Al-Najjar, 2011, Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling, Eur. J. Med. Chem., 46, 2513, 10.1016/j.ejmech.2011.03.040

Bénardeau, 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

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

Berthold, 2007, KNIME: the Konstanz information miner

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

Carrieri, 2013, Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists, Eur. J. Med. Chem., 63, 321, 10.1016/j.ejmech.2013.02.015

Casimiro-Garcia, 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

Casimiro-Garcia, 2009, Synthesis and evaluation of novel α-heteroaryl-phenylpropanoic acid derivatives as PPARα/γ dual agonists, Bioorg. Med. Chem., 17, 7113, 10.1016/j.bmc.2009.09.001

Chigurupati, 2015, A step ahead of PPARγ full agonists to PPARγ partial agonists: therapeutic perspectives in the management of diabetic insulin resistance, Eur. J. Pharmacol., 755, 50, 10.1016/j.ejphar.2015.02.043

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

Devasthale, 2007, Discovery of tertiary aminoacids as dual PPARα/γ agonists-I, Bioorg. Med. Chem. Lett., 17, 2312, 10.1016/j.bmcl.2007.01.060

Dixit, 2008, QSAR analysis of PPAR-γ agonists as anti-diabetic agents, Eur. J. Med. Chem., 43, 73, 10.1016/j.ejmech.2007.03.004

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

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

Henke, 1998, N-(2-benzoylphenyl)--tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents, J. Med. Chem., 41, 5020, 10.1021/jm9804127

Klebe, 1998, Comparative molecular similarity indices analysis: CoMSIA, vol. 3, 87

Krewski, 2010, Toxicity testing in the 21st century: a vision and a strategy, J. Toxicol. Environ. Health B Crit. Rev., 13, 51, 10.1080/10937404.2010.483176

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

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

Landesmann, 2012

Liao, 2004, 3D QSAR studies on peroxisome proliferator-activated receptor gamma agonists using CoMFA and CoMSIA, J. Mol. Modell., 10, 165, 10.1007/s00894-003-0175-4

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

Lu, 2006, Design, synthesis, and evaluation of 2-alkoxydihydrocinnamates as PPAR agonists, Bioorg. Med. Chem. Lett., 16, 915, 10.1016/j.bmcl.2005.10.104

MOE (Molecular Operating Environment) version 2014.091, 2015. Chemical Computing Group Inc. http://www.chemcomp.com.

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

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

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

Melagraki, 2009, Predictive QSAR workflow for the in silico identification and screening of novel HDAC inhibitors, Mol. Divers., 13, 301, 10.1007/s11030-009-9115-2

Mostrag-Szlichtyng, 2014, Data mining approach to formulate alerting chemotypes for liver steatosis/steatohepatitis/fibrosis, Poster presented at SOT 53rd Annual Meeting, 24–27 March 2014

Mueller, J.J., Schupp, M., Unger, T., Kintscher, U., Heinemann, U., 2010. Ligand binding domain of human PPARgamma in complex with the agonist pioglitazone. doi: 10.2210/pdb2xkw/pdb.

Mysinger, 2012, Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking, J. Med. Chem., 55, 6582, 10.1021/jm300687e

Netzeva, 2005, Current status of methods for defining the applicability domain of (quantitative) structure-activity relationships. The report and recommendations of ECVAM Workshop 52, Altern. Lab. Anim., 33, 155, 10.1177/026119290503300209

OECD, 2013

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

Ohashi, 2013, Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility, Bioorg. Med. Chem., 21, 2319, 10.1016/j.bmc.2013.02.003

Otake, 2011, A novel series of (S)-2,7-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: peroxisome proliferator-activated receptor α/γ dual agonists with protein-tyrosine phosphatase 1B inhibitory activity, Chem. Pharm. Bull., 59, 1233, 10.1248/cpb.59.1233

Otake, 2011, 2-Acyl-tetrahydroisoquinoline-3-carboxylic acids: lead compounds with triple actions, peroxisome proliferator-activated receptor α/γ agonist and protein-tyrosine phosphatase 1B inhibitory activities, Chem. Pharm. Bull. (Tokyo), 59, 876, 10.1248/cpb.59.876

Otake, 2012, Novel (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: peroxisome proliferator-activated receptor γ selective agonists with protein-tyrosine phosphatase 1B inhibition, Bioorg. Med. Chem., 20, 1060, 10.1016/j.bmc.2011.11.035

Patlewicz, 2015, Proposing a scientific confidence framework to help support the application of adverse outcome pathways for regulatory purposes, Regul. Toxicol. Pharmacol., 71, 463, 10.1016/j.yrtph.2015.02.011

Rücker, 2006, 2D QSAR of PPARgamma agonist binding and transactivation, Bioorg. Med. Chem., 14, 5178, 10.1016/j.bmc.2006.04.005

Rabinowitz, 2008, Computational molecular modeling for evaluating the toxicity of environmental chemicals: prioritizing bioassay requirements, Environ. Health Perspect., 116, 573, 10.1289/ehp.11077

SYBYL-X, version 2.1, Tripos International, 2013. https://www.certara.com/.

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

Sauerberg, 2003, Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo, J. Med. Chem., 46, 4883, 10.1021/jm0309046

Sauerberg, 2005, Structure-activity relationships of dimeric PPAR agonists, Bioorg. Med. Chem. Lett., 15, 1497, 10.1016/j.bmcl.2004.12.084

Shah, 2008, CoMFA analysis of dual/multiple PPAR activators, Eur. J. Med. Chem., 43, 2784, 10.1016/j.ejmech.2008.01.017

Sundriyal, 2009, Sum of activities as dependent parameter: A new CoMFA-based approach for the design of pan PPAR agonists, Eur. J. Med. Chem., 44, 42, 10.1016/j.ejmech.2008.03.014

Tropsha, 2003, The importance of being earnest: validation is the absolute essential for successful application and interpretation of QSPR models, QSAR Comb. Sci., 2, 69, 10.1002/qsar.200390007

Tsakovska, 2014, Molecular modelling study of the PPARγ receptor in relation to the mode of action/adverse outcome pathway framework for liver steatosis, Int. J. Mol. Sci., 15, 7651, 10.3390/ijms15057651

Vedani, 2007, Predicting the toxic potential of drugs and chemicals in silico: a model for the peroxisome proliferator-activated receptor γ (PPAR γ), Toxicol. Lett., 173, 17, 10.1016/j.toxlet.2007.06.011

Vidović, 2011, A combined ligand- and structure-based virtual screening protocol identifies submicromolar PPARγ partial agonists, ChemMedChem, 6, 94, 10.1002/cmdc.201000428

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

Yang, 2015, New publicly available chemical query languag. CSRML, to support chemotype representations for application to data mining and modeling, J. Chem. Inf. Modell., 55, 510, 10.1021/ci500667v

Ye, 2010, Synthesis and structure–activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel, potent PPAR’ selective activators-PPAR’ and PPARα selectivity modulation, Bioorg. Med. Chem. Lett., 20, 2933, 10.1016/j.bmcl.2010.03.019

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