Structural basis for the design of PPAR-γ ligands: A survey on quantitative structure- activity relationships

Mini-Reviews in Medicinal Chemistry

Volumn 9, Issue 9, 2009, Pages 1075-1083

  Giaginis, Costas ^a,b   Theocharis, Stamatios ^b   Tsantili Kakoulidou, Anna ^a  

^a UNIVERSITY OF ATHENS   (Greece)

^b UNIVERSITY OF ATHENS MEDICAL SCHOOL   (Greece)

Author keywords

2D QSAR; 3D QSAR; Drug design; Mechanism of action; PPAR ; Type II diabetes

Indexed keywords

15 DEOXY DELTA12,14 PROSTAGLANDIN J2; 2,4 THIAZOLIDINEDIONE DERIVATIVE; CHIGLITAZAR; FARGLITAZAR; HORMONE RECEPTOR STIMULATING AGENT; NETOGLITAZONE; NITROLINOLEIC ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIOGLITAZONE; RAGAGLITAZAR; ROSIGLITAZONE; TESAGLITAZAR; UNCLASSIFIED DRUG; LIGAND;

BINDING AFFINITY; CLINICAL TRIAL; COMPARATIVE MOLECULAR FIELD ANALYSIS; COMPARATIVE MOLECULAR SIMILARITY INDICES ANALYSIS; DRUG DESIGN; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG STRUCTURE; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PLEIOTROPY; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; UNSPECIFIED SIDE EFFECT; X RAY CRYSTALLOGRAPHY; ANIMAL; CHEMISTRY; DRUG POTENTIATION; METABOLISM; PROTEIN BINDING;

ANIMALS; DRUG DESIGN; HUMANS; LIGANDS; PPAR GAMMA; PROTEIN BINDING; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 70349571579     PISSN: 13895575     EISSN: None     Source Type: Journal    
DOI: 10.2174/138955709788922601     Document Type: Review

References (103)

1. Staels, B.; Fruchart, J.C. Therapeutic roles of peroxisome proliferators activated receptor agonists. Diabetes, 2005, 54, 2460-2470
2. Lenhard, J.M. PPAR gamma/RXR as a molecular target for diabetes. Receptors Channel, 2001, 7, 249-258
3. Rieusset, J.; Andreelli, F.; Auboeuf, D.; Roques, M.; Vallier, P.; Riou, J. P.; Auwerx, J.; Laville, M.; Vidal, H. Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor- gamma in human adipocytes Diabetes, 1999, 48, 699-705. (Pubitemid 29153067)
4. Steinbrook, R. Facing the diabetes epidemic - mandatory reporting of glycosylated hemoglobin values in New York City, N. Engl. J. Med., 2006, 354, 545-548.
5. Wysowski, D.K.; Armstrong, G.; Governale, L. Rapid increase in the use of oral antidiabetic drugs in the United States, 1990-2001. Diabetes Care, 2003, 26, 1852-1855.
6. Hansch, C.; Leo, A. Exploring QSAR: fundamentals and applications in chemistry and biology. American Chemical Society: Washington, 1995.
7. Wermuth, C. The impact of QSAR and CCAD methods in Drug Discovery, in: Rational Approaches to Drug Design. Holtje, H.D.; Sippl, W. Eds, Prous Science, 2001.
8. Testa, B.; Vistoli, G.; Pedretti, A. Musings on ADME predictions and structure - activity relations. Chem. Biodivers., 2005, 2, 1411-1427. (Pubitemid 41762895)
9. Ooms, F. Molecular modeling and computer aided drug design. Examples of their applications in medicinal chemistry. Curr. Med. Chem., 2000, 7, 141-158 (Pubitemid 30396444)
10. Tsantili-Kakoulidou, A. QSAR: A tool in Drug Design or a computer game. A dialectic view. Pharmakeftiki, 2008, 21, 45-56.
11. Kliewer, S.A.; Forman, B.M.; Blumberg, B.; Ong, E.S.; Borgmeyer, U.; Mangelsdorf, D.J.; Umesono, K.; Evans, R.M. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA, 1994, 91, 7355-7359.
12. Nolte, R.T.; Wisely, G.B.; Westin, S.; Cobb, J.E.; Lambert, M.H.; Kurokawa, R.; Rosenfeld, M.G.; Willson, T.M.; Glass, C.K.; Milburn, M.V. Ligand binding and co-activator assembly of the peroxisome proliferators activated receptor-γ. Nature, 1998, 395, 137-143. (Pubitemid 28425645)
13. Desvergne, B.; Wahli, W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev., 1999, 20, 649-688. (Pubitemid 30650602)
14. Braissant, O.; Foufelle, F.; Scotto, C.; Dauça, M.; Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-α, β- and -γ in the adult rat. Endocrinology, 1996, 137, 354-366. (Pubitemid 26005011)
15. Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem., 2000, 43, 527-550. (Pubitemid 30127149)
16. Vidal-Puig, A.J.; Considine, R.V.; Jimenez-Liñan, M.; Werman, A.; Pories, W.J.; Caro, J.F.; Flier, J.S. Peroxisome proliferatoractivated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J. Clin. Invest., 1997, 99, 2416-2422 (Pubitemid 27227719)
17. Duval, C.; Müller, M.; Kersten, S. PPARα and dyslipidemia. Biochim. Biophys. Acta, 2007, 1771, 961-971.
18. Ichihara, S.; Obata, K.; Yamada, Y.; Nagata, K.; Noda, A.; Ichihara, G.; Yamada, A.; Kato, T.; Izawa, H.; Murohara, T.; Yokota M. Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors. J. Mol. Cell Cardiol., 2006, 41, 318-329 (Pubitemid 44080222)
19. Barish, G.D.; Narkar, V.A.; Evans, R.M. PPAR delta: a dagger in the heart of the metabolic syndrome. J. Clin. Invest., 2006, 116, 590-597 (Pubitemid 43326863)
20. Lee, C.H.; Chawla, A.; Urbiztondo, N.; Liao, D.; Boisvert, W.A.; Evans, R.M.; Curtiss, L.K. Transcriptional repression of atherogenic inflammation: modulation by PPAR delta. Science, 2003, 302, 453-457
21. Welch, J.S.; Ricote, M.; Akiyama, T.E.; Gonzalez, F.J.; Glass, C.K. PPAR gamma and PPAR delta negatively regulate specific subsets of lipopolysaccharide and IFNgamma target genes in macrophages. Proc. Natl. Acad. Sci., 2003, 100, 6712-6717
22. Graham, T.L.; Mookherjee, C.; Suckling, K.E.; Palmer, C.N.; Patel, L. The PPAR delta agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice. Atherosclerosis, 2005, 181, 29-37. (Pubitemid 40804690)
23. Blaschke, F.; Takata, Y.; Caglayan, E.; Law, R.E.; Hsueh, W.A. Obesity, Peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes. Arterioscler. Thromb. Vasc. Biol., 2006, 26, 28-40. (Pubitemid 43732225)
24. Vidal-Puig, A.; Jimenez-Liñan, M.; Lowell, B.B.; Hamann, A.; Hu, E.; Spiegelman, B.; Flier, J.S.; Moller, D.E. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J. Clin. Invest., 1996, 97, 2553-2561 (Pubitemid 26187343)
25. Fajas, L.; Auboeuf, D.; Raspé, E.; Schoonjans, K.; Lefebvre, A.M.; Saladin, R.; Najib, J.; Laville, M.; Fruchart, J.C.; Deeb, S.; Vidal-Puig, A.; Flier, J.; Briggs, M.R.; Staels, B.; Vidal, H.; Auwerx, J. The organization, promoter analysis, and expression of the human PPAR gamma gene. J. Biol. Chem., 1997, 272, 18779-18789 (Pubitemid 27318225)
26. Theocharis, S.; Margeli, A.; Viehl, P.; Kouraklis, G. Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators. Cancer Treat. Rev., 2004, 30, 545-554. (Pubitemid 39157854)
27. Hamerman, D. Osteoporosis and atheroslerosis: biological linkages and the emergence J. Clin. Invest., 1997, 99, 2416-2422
28. Giaginis, C.; Tsantili-Kakoulidou, A.; Theocharis, S. Peroxisome proliferator-activated receptor-gamma ligands as bone turnover modulators. Expert Opin. Investig. Drugs, 2007, 16, 195-207. (Pubitemid 46206633)
29. Giaginis, C.; Spanopoulou, E.; Theocharis, S. PPAR-γ signaling pathway in placental development and function: A potential therapeutic target in the treatment of gestational diseases. Expert Opin. Ther.Target, 2008, 12, 1049-1063
30. Giaginis, C.; Tsourouflis, G.; Theocharis, S. Peroxisome Proliferator- Activated Receptor-γ (PPAR-γ) ligands: novel pharmacological agents in the treatment of ischemia reperfusion injury. Curr. Mol. Med., 2008, 8, 562-579.
31. Murphy, G.J.; Holder, J.C. PPAR-gamma agonists: therapeutic role in diabetes, inflammation and cancer. Trends Pharmacol Sci., 2000, 21, 469-474
32. Fenner, M.H.; Elstner, E. Peroxisome proliferator-activated receptor- gamma ligands for the treatment of breast cancer. Expert Opin. Investig. Drugs, 2005, 6, 557-568. (Pubitemid 40895186)
33. Wayman, N.S.; Hattori, Y.; McDonald, M.C.; Mota-Filipe, H.; Cuzzocrea, S.; Pisano, B.; Chatterjee, P.K.; Thiemermann, C. Ligands of the peroxisome proliferator-activated receptors (PPARgamma and PPAR-alpha) reduce myocardial infarct size. FASEB J., 2002, 16, 1027-1040 (Pubitemid 34753509)
34. Henke, B. R. Peroxisome proliferator-activated receptor α/γ dual agonists for the treatment of type 2 diabetes. J. Med. Chem., 2004, 47, 4118-4127 (Pubitemid 39045415)
35. Lohray, B. B.; Bhushan, V.; Bajji, A. C.; Kalchar, S.; Poondra, R. R.; Padakanti, S.; Chakrabarti, R.; Vikramadityan, R. K.; Mishra, P.; Juluri, S.; Mamidi, N. V. S. R.; Rajagopalan, R. (-)3-[4-[2- (Phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid [(-) DRF 2725]: A dual PPAR agonist with potent antihyperglycemic and lipid modulating acitivity. J. Med. Chem., 1999, 42, 2569-2581
36. Sauerberg, P.; Pettersson, I.; Jeppesen, L.; Bury, P. S.; Mogensen, J. P.; Wassermann, K.; Brand, C. L.; Sturis, J.; Woldike, H. F.; Fleckner, J.; Andersen, A. T.; Mortensen, S. B.; Svensson, L. A.; Rasmussen, H. B.; Lehmann, S. V.; Polivka, Z.; Sindelar, K.; Panajotova, V.; Ynddal, L.; Wulff, E.M. Novel tricyclic-ralkoxyphenylpropionic acids: dual PPARα/γ agonists with hypolipidemic and antidiabetic activity. J. Med. Chem., 2002, 45, 789-804.
37. Ebdrup, S.; Pettersson, I.; Rasmussen, H. B.; Deussen, H.; Jensen, A. F.; Mortensen, S. B.; Fleckner, J.; Pridal, L.; Nygaard, L.; Sauerberg, P. Synthesis and biological and structural characterzation of the dual-acting peroxisome proliferator- activated receptor α/γ agonist ragaglitazar. J. Med. Chem., 2003, 46, 1306-1317
38. Tenenbaum, A.; Motro, M.; Fisman, E.Z. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovasc. Diabetol., 2005, 4, 1-5.
39. Nagasawa, T.; Inada, Y.; Nakano, S.; Tamura, T.; Takahashi, T.; Maruyama, K.; Yamazaki, Y.; Kuroda, J.; Shibata, N. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur. J. Pharmacol., 2006, 536, 182-191
40. Rubenstrunk, A.; Hanf, R.; Hum, D. W.; Fruchart, J. C.; Staels, B. Safety issues and prospects for future generations of PPAR modulators. Biochim. Biophys. Acta, 2007, 1771, 1065-1081 (Pubitemid 47208546)
41. Montanari, R.; Saccoccia, F.; Scotti, E.; Crestani, M.; Godio, C.; Gilardi, F.; Loiodice, F.; Fracchiolla, G.; Laghezza, A.; Tortorella, P.; Lavecchia, A.; Novellino, E.; Mazza, F.; Aschi, M.; Pochetti, G. Crystal structure of the peroxisome proliferator-activated receptor (PPARγ) ligand binding domain complexed with a novel partial agonist: A new region of the hydrophobic pocket could be exploited for drug design. J. Med. Chem., 2008, 51, 7768-7776
42. Tugwood, J.D.; Issemann, I.; Anderson, R.G.; Bundell, K.R.; McPheat, W.L.; Green, S. The mouse peroxisome proliferator activated receptor recognizes a response element in the 5′ flanking sequence of the rat acyl CoA oxidase gene. EMBO J., 1992 11, 433-439
43. Berger, J.; Moller, D.E. The mechanisms of action of PPARs. Ann. Rev. Med., 2002, 53, 409-435.
44. Feige, J.N.; Gelman, L.; Michalik, L.; Desvergne, B.; Wahli, W. From molecular action to physiological outputs: Peroxisome proliferator- activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog. Lipid Res., 2006, 45, 120-159. (Pubitemid 43248732)
45. Nosjean, O.; Boutin, J.A. Natural ligands of PPARgamma: are prostaglandin J(2) derivatives really playing the part? Cell Signal., 2002, 14, 573-583
46. Ferry, G.; Bruneau, V.; Beauverger, P.; Goussard, M.; Rodriguez, M.; Lamamy, V.; Dromaint, S.; Canet, E.; Galizzi, J.-P.; Boutin, J. A. Binding of prostaglandins to human PPAR-γ: tool assessment and new natural ligands. Eur. J. Pharmacol., 2001, 77, 417-489
47. Schopfer, F. J.; Lin, Y.; Baker, P. R. S.; Cui, T.; Garcia-Barrio, M.; Zhang, J.; Chen, K.; Chen, Y. E.; Freeman, B. A. Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor gamma ligand. Proc. Natl. Acad. Sci. USA, 2005, 102, 2340-2345 (Pubitemid 40279377)
48. Uppenberg, J.; Svensson, C.; Jaki, M.; Bertilsson, G.; Jendeberg, L.; Berkenstam, A. Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma. J. Biol. Chem., 1998, 273, 31108-31112 (Pubitemid 28533120)
49. Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28, 235-242
50. Berman, H.M.; Battistuz, T.; Bhat, T.N.; Bluhm, W.F.; Bourne, P.E.; Burkhardt, K.; Feng, Z.; Gilliland, G.L.; Iype, L.; Jain, S.; Fagan, P.; Marvin, J.; Padilla, D.; Ravichandran, V.; Schneider, B.; Thanki, N.; Weissig, H.; Westbrook, J.D.; Zardecki, C. The protein data bank. Acta Crystallogr. D, 2002, 58, 899-907.
51. Li, Y.; Choi, M.; Suino, K.; Kovach, A.; Daugherty, J.; Kliewer, S.A.; Xu, H.E.. 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, 2005, 102, 9505-9510
52. Xu, H.E.; Lambert, M.H.; Montana, V.G.; Plunket, K.D.; Moore, L.B.; Collins, J.L.; Oplinger, J.A.; Kliewer, S.A.; Gampe, R.T. Jr.; McKee, D.D.; Moore, J.T.; Willson, T.M. Structural determinants of ligand binding selectivity between the peroxisome proliferatoractivated receptors. Proc. Natl. Acad. Sci. USA, 2001, 98, 13919-13924 (Pubitemid 33115999)
53. Gampe Jr., R.T.; Montana, V.G.; Lambert, M.H.; Miller, A.B.; Bledsoe, R.K.; Milburn, M.V.; Kliewer, S.A.; Willson, T.M.; Xu, H.E. Asymmetry in the PPARγ/RXRR crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol. Cell, 2000, 5, 545-555
54. Bourguet, W.; Ruff, M.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature, 1995, 375, 377-382
55. Renaud, J.; Rochel, N.; Ruff, M.; Vivat, V.; Chambon, P., Gronemeyer, H.; Moras, D. Crystal structure of the RAR-[gamma] ligand-binding domain bound to all-trans retinoic acid. Nature, 1995, 378, 681-689 (Pubitemid 3009996)
56. Zoete, V.; Grosdidier, A.; Michielin, O. Peroxisome proliferatoractivated receptor structures: Ligand specificity, molecular switch and interactions with regulators. Biochim. Biophys. Acta, 2007, 1771, 915-925 (Pubitemid 47208545)
57. Xu, H.E.; Lambert, M.H.; Montana, V.G.; Parks, D.J.; Blanchard, S.G.; Brown, P.J.; Sternbach, D.D.; Lehmann, J.M.; Wisely, W.G.; Willson, T.M.; Kliewer, S.A.; Milburn, M.V. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell, 1999, 3, 397-403.
58. Lu, I.-L.; Huang, C.-F.; Peng, Y.-H.; Lin, Y.-T.; Hsieh, H.-P.; Chen, C.-T.; Lien, T.-W.; Lee, H.-J.; Mahindroo, N.; Prakash, E.; Yueh, A.; Chen, H.-Y.; Goparaju, C.M.V.; Chen, X.; Liao, C.-C.; Chao, Y.-S.; Hsu, J.-T.A.; Wu, S.-Y. Structure-based drug design of a novel family of PPAR partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities. J. Med. Chem., 2006, 49, 2703-2712
59. Burgermeister, E.; Schnoebelen, A.; Flament, A.; Benz, J.; Stihle, M.; Gsell, B.; Rufer, A.; Ruf, A.; Kuhn, B.; Marki, H.P.; Mizrahi, J.; Sebokova, E.; Niesor, E.; Meyer, M. A novel partial agonist of peroxisome proliferators activated receptor-gamma (PPAR gamma) recruits PPAR gamma-Coactivator-1alpha, prevents triglyceride accumulation, and potentiates insulin signaling in vitro. Mol. Endocrinol., 2006, 20, 809-830.
60. Parks, D. J.; Tomkinson, N. C. O.; Villeneuve, M. S.; Blanchard, S. G.; Willson, T. M. Differential activity of rosiglitazone enantiomers at PPARγ. Bioorg. Med. Chem. Lett., 1998, 8, 3657-3658
61. Haigh, D.; Allen, G.; Birrell, H. C.; Buckle, D. R.; Cantello, B. C. C.; Eggleston, D. S.; Haltiwanger, R. C.; Holder, J. C.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Sime, J. T.; Smith, S. A.; Sweeney, J. D. Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-betaphenylpropanoic acids. Bioorg. Med. Chem., 1999, 7, 821-830 (Pubitemid 29238077)
62. Sohda, T.; K., M.; Imamiya, E.; Sugiyama, Y.; Fujita, T.; Kawamatsu, Y. Studies on Antidiabetic Agents. II. Synthesis of 5-[4-(1- Methylcyclohexyl methoxybenzyl] thiazolidine-2,4-dione (ADD- 3878) and its Derivatives. Chem. Pharm. Bull., 1982, 3580-3600.
63. Dow, R. L.; Bechle, B. M.; Chou, T. T.; Clark, D. A.; Hulin, B.; Stevenson, R. W. Benzyloxazolidine-2,4-dines as Potent Hypoglycemic Agents. J. Med. Chem., 1991, 34, 1538-1554
64. Momose, Y.; Maekawa, T.; Yamano, T.; Kawada, M.; Odaka, H.; Ikeda, H.; Sohda, T. Novel 5-substituted 2,4-thiazolidinedione and 2,4-oxazolidinedione derivatives as insulin sensitizers with antidiabetic activities. J. Med. Chem., 2002, 45, 1518-1534 (Pubitemid 34246115)
65. Chang, F. Evolution of peroxisome proliferator-activated receptor agonists. Ann. Pharmacother., 2007, 41, 973-983. (Pubitemid 46917624)
66. Balakumar, P.; Rose, M.; Ganti, S. S.; Krishan, P.; Singh, M. PPAR dual agonists: are they opening pandora's box? Pharmacol. Res., 2007, 56, 91-98. (Pubitemid 47304493)
67. Watkins, P. B.; Whitecomb, R. Hepatic dysfunction associated with troglitazone. N. Engl. J. Med., 1998, 338, 916-917
68. Patel, C.; Wyne, K.L.; McGuire, D.K. Thiazolidinediones, peripheral oedema and congestive heart failure: what is the evidence? Diab. Vasc. Dis. Res., 2005, 2, 61-66
69. Lehmann, J.M.; Lenhard, J.M.; Oliver, B.B.; Ringold, G.M.; Kliewer, S.A. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem., 1997, 272, 3406-3410 (Pubitemid 27066837)
70. Acton, J.J.III; Black, R.M.; Jones, A.B.; Moller, D.E.; Colwell, L.; Doebber, T.W.; Macnaul, K.L.; Berger, J.; Wood, H.B. Benzoyl 2- methyl indoles as selective PPAR modulators. Bioorg. Med. Chem. Lett., 2005, 15, 357-362
71. Dropinski, J.F.; Akiyama, T.; Einstein, M.; Habulihaz, B.; Doebber, T.; Berger, J.P.; Meinke, P.T.; Shi, G.Q. Synthesis and biological activities of novel aryl indole-2-carboxylic acid analogs as PPARγ partial agonists. Bioorg. Med. Chem. Lett., 2005, 15, 5035-5038
72. Kuhn, B.; Hilpert, H.; Benz, J.; Binggeli, A.; Grether, U.; Humm, R.; Marki, H.P.; Meyer, M.; Mohr, P. Structure-based design of indole propionic acids as novel PPARα/γ co-agonists. Bioorg. Med. Chem. Lett., 2006, 16, 4016-4020 (Pubitemid 43903212)
73. Mahindroo, N.; Wang, C.C.; Liao, C.C.; Huang, C.F.; Lu, I.L.; Lien, T.W.; Peng, Y.H.; Huang, W.J.; Lin, Y.T.; Hsu, M.C.; Lin, C.H.; Tsai, C.H.; Hsu, J.T.; Chen, X.; Lyu, P.C.; Chao, Y.S.; Wu, S.Y.; Hsieh, H.P. Indol-1-yl acetic acids as peroxisome proliferator- activated receptor agonists: design, synthesis, structural biology and molecular docking studies. J. Med. Chem., 2006, 49, 1212-1216
74. Cramer, R. D. III; Patterson, D. E.; Bunce, J. D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110, 5959-5967
75. Hariprasad, V.; Kulkarni, V. M. J. A proposed common spatial pharmacophore and the corresponding active conformations of some peptide leukotriene receptor antagonists. Comput. Aided Mol. Des., 1996, 10, 284-292
76. Kulkarni, S.S.; Gediya, L.K.; Kulkarni, V.M. Three-dimensional Quantitative Structure Activity Relationships (3D-QSAR) of antihyperglycemic agents. Bioorg. Med. Chem., 1999, 7, 1475-1485
77. Klebe, G. Comparative Molecular Similarity Indices Analysis: CoMSIA. Perspect. Drug Discov. Des., 1998, 12, 87-104.
78. Klebe, G.; Abraham, U.; Mietzner, T. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J. Med. Chem., 1994, 37, 4130-4146 (Pubitemid 24379702)
79. Liao, C. Z.; Xie, A. H.; Shi, L. M.; Zhou, J. J.; Lu, X. P. 3D QSAR studies on peroxisome proliferator-activated receptor gamma agonists using CoMFA and CoMSIA. J. Mol. Model., 2004 10, 165-177 (Pubitemid 38821252)
80. Liao, C. Z.; Xie, A. H.; Shi, L. M.; Zhou, J. J.; Lu, X. P. Eigenvalue analysis of peroxisome proliferator-activated receptor- agonists. J. Chem. Inf. Comput. Sci., 2004, 44, 230-238
81. Ferguson, A. M.; Heritage, T.; Jonathon, P.; Pack, S. E.; Philips, L.; Rogan, J.; Snaith, P.J. EVA: A new theoretically based molecular descriptor for use in QSAR/QSPR analysis. J. Comput.-Aided. Mol. Des., 1997, 11, 143-152
82. Turner, D. B.; Willett, P. Evaluation of the EVA descriptor for QSAR studies: 3. The use of a genetic algorithm to search for models with enhanced predictive properties (EVA-GA). J. Comput. Aided. Mol. Des., 2000, 14, 1-21. (Pubitemid 30103819)
83. Rathi, L.; Kashaw, S. K.; Dixit, A.; Pandey, G.; Saxena, A. K Pharmacophore identification and 3D-QSAR studies in N-(2- benzoyl phenyl)-L-tyrosines as PPARγ agonists. Bioorg. Med. Chem., 2004, 12, 63-69. (Pubitemid 38096218)
84. Kashaw, S. K.; Rathi, L. G.; Mishra, P.; Saxena, A. K. Development of 3D-QSAR models in cyclic ureidobenzenesulfonamides: human beta3-adrenergic receptor agonist. Bioorg. Med. Chem. Lett., 2003, 13, 2481-2484
85. Arockia Babu, M.; Shakya, N.; Prathipati, P.; Kaskhedikar, S. G.; Saxena, A. K. Development of 3D-QSAR models for 5- lipoxygenase antagonists: chalcones. Bioorg. Med. Chem., 2002, 10, 4035-4041
86. Kurogi, Y. Three-dimensional quantitative structure-activity relationships (3D-QSAR) of antidiabetic thiazolidinediones. Drug Des. Discov., 1999, 16, 109-118 (Pubitemid 29450339)
87. Khanna, S.; Sobhia, M. E.; Bharatam P. V. Additivity of molecular fields: CoMFA study on dual activators of PPAR and PPAR . J. Med. Chem., 2005, 48, 3015-3025 (Pubitemid 40548113)
88. Sundriyal, S.; Bharatam, P.V. 'Sum of activities' as dependent parameter: A new CoMFA-based approach for the design of pan PPAR agonists. Eur. J. Med. Chem., 2009 44, 42-53.
89. Hopfinger, A.J.; Wang, S.; Tokarski, J.S.; Jin, B.; Albuquerque, M.; Madhav, P.J.; Duraiswami, C. Construction of 3D-QSAR models using 4D-QSAR analysis formalism. J. Am. Chem. Soc., 1997, 119, 10509-10524 (Pubitemid 27487990)
90. Vedani, A.; Dobler, M.; Lill, M.A. Combining protein modelling and 6D-QSAR-simulating the binding of structurally diverse ligands to the estrogen receptor. J. Med. Chem., 2005, 48, 3700-3703
91. Vedani, A.; Descloux, A.-V.; Spreafico, M.; Ernst, B. Predicting the toxic potential of drugs and chemicals in silico: A model for the peroxisome proliferator-activated receptor γ (PPAR γ). Toxicol. Lett., 2007, 173, 17-23 (Pubitemid 47211705)
92. Rücker, C.; Scarsi, M.; Meringer, M. 2D QSAR of PPARγ agonist binding and transactivation. Bioorg. Med. Chem., 2006, 14, 5178-5195 (Pubitemid 43903265)
93. Xue L.; Bajorath J. Accurate partitioning of compounds belonging to diverse activity classes. J. Chem. Inf. Comput. Sci., 2002, 42, 757-764 (Pubitemid 35355284)
94. Dixit, A.; Saxena, A.K. QSAR analysis of PPAR-gamma agonists as anti-diabetic agents. Eur. J. Med. Chem., 2008, 43, 73-80.
95. Giaginis, C.; Theocharis, S.; Tsantili-Kakoulidou, A. Application of multivariate data analysis for modeling receptor binding and gene transactivation of tyrosine-based ppar-γ ligands, Chem. Biol. Drug Des., 2008, 72, 257-264
96. Eriksson, L.; Johansson, E.; Kettaneh-Wold, N.; Wold, S. Multiand Megavariate Data Analysis, Principles and Applications, Umetrics AB, Umea, Sweden, 2001.
97. Eriksson, L.; Johansson, E. Multivariate design and modeling in QSAR. Chemometr. Intell. Lab. Syst., 1996, 34, 1-19.
98. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev., 1997, 23, 3-25.
99. Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45, 2615-2623
100. Giaginis, C.; Theocharis, S.; Tsantili-Kakoulidou, A. A QSAR study on indole-based PPAR-γ agonists with respect to receptor binding and transactivation data. QSAR Comb. Sci. in press
101. Giaginis, C.; Zira, A.; Theocharis, S.; Tsantili-Kakoulidou, A. Property distribution in the chemical space of PPAR-γ agonists: Evaluation of drug-like characteristics. Rev. Clin. Pharmacol. Pharmacokinet. Intern. Ed., 2008, 22, 366-368 (Pubitemid 351831309)
102. Giaginis, C.; Theocharis, S.; Tsantili-Kakoulidou, A. A consideration of PPAR-γ ligands in respect to lipophilicity: Current trends and perspectives. Expert Opin. Investig. Drugs, 2007, 16, 413-417 (Pubitemid 46554460)
103. Kumar, P.M.; Hemalatha, R.; Mahajan, S.C.; Karthikeyan, C.; Moorthy, N.S.; Trivedi, P. Quantitative structure-activity analysis of 2-alkoxydihydrocinnamates as PPAR alpha/gamma dual agonist. Med. Chem., 2008, 4, 273-277 (Pubitemid 351827302)