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研究生： 彭懿慧
Peng, Yi-Hui
論文名稱： Structure based drug design of peroxisome proliferator-activated receptor (PPAR) agonists
結構為主的藥物設計輔助抗糖尿病藥物的設計與發展
指導教授： 呂平江
Lyu, Ping-Chiang
伍素瑩
Wu, Su-Ying
口試委員:
學位類別： 博士
Doctor
系所名稱： 生命科學暨醫學院 - 生物資訊與結構生物研究所
Institute of Bioinformatics and Structural Biology
論文出版年： 2010
畢業學年度： 99
語文別： 英文
論文頁數： 209
中文關鍵詞： 結構為主的藥物設計 、過氧化酶增生子活化接受器 、結構生物學 、X -ray 結晶學
外文關鍵詞： structure based drug design, peroxisome proliferator-activated receptors, structure biology, X-ray crystallography
相關次數： 點閱：2  下載：0 
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    • Peroxisome proliferator-activated receptors (PPARs) were the drug targets with different activation mechanism. Activation of PPARγ would improve the insulin sensitivity and thus was the action site of antidiabetes TZD drugs. To develop safer and effective antidiabetic drug in our study, structure based drug design (SBDD) was applied to help to design the antidiabetic drugs.

    We subcloned different fragments of PPARγ ligand binding domain (LBD) for co-crystallization with different agonists. The fragments: amino acids 252-477, 175 - 477, and 207 - 477 were expressed and purified. The clone of amino acids 252 - 477 produced insoluble form mostly and was difficult to purify. The other two clones produced large amount of soluble proteins and were able to crystallization. In X-ray data collection, the co-crystals of fragment 207 - 477 a. a. complexing with different agonists diffracted to 1.9 - 2.5 Å of resolution that was better than that of the fragment of 175 - 477 a. a diffracted to 2.8 - 3.0 Å.

    A potent PPARα/γ/δ pan agonist BPR1H036 (PPARα/γ/δ EC50 = 14/230/10 nM), a novel series of indole based compound with a benzisoxazole tail, was the lead in this study. X-ray structure biology showed that the carboxylic acid head of BPR1H036 formed four conserved H-bonds and the indole ring contributed to strong hydrophobic interactions with PPARγ. Thus, the indole head moiety played an important role in binding to the protein.

    Followed, the diverse tail parts of indole-based agonists were studied. Compound BPR1H172 (PPARα/γ/δ EC50 = 8/70/500 nM), with the n-propyl substituted naphthophenone tail part attaching to 5-position of indole through a linker, showed more potent PPAR pan activity than lead. The structure biology showed that the naphthophenone tail makes intensive hydrophobic interactions with PPARγ; the distance between the acidic group and linker were also important for the potency.

    In addition, we also explained the structure-activity relationships (SAR) of the series of indole based compounds with different selectivity and potency by structure biology. When the indole ring of head was reversed from the orientation of BPR1H172 to BPR1H201 (PPARα/γ/δ EC50 = 32/2210/>10000 nM), the activity of PPARγ was decreased due to the lose of H-binds. By adding the fibrate moiety to the head of BPR1H201, BPR1H183 (PPARα/γ/δ EC50 = 123/650/>10000 nM) recovered PPARγ activity by reforming four conserved H-bonds.

    Further modifications of hydrophobic tail parts of BPR1H183 to improve PPARγ potency, we found that compound BPR1H378 (PPARα/γ/δ EC50 = 1920/120/>10000 nM) contained the most potent and selective 4-phenyl-benzophenone tail with the lowest binding energy, which contributed to the improved PPARγ potency. Ring expansion of the indole head resulted in compound BPR1H385 (PPARα/γ/δ EC50 = 3990/50/>10000 nM) forming more extensive hydrophobic interactions with protein and thus increased the PPARγ activity.

    Based on the SAR and structure biology analysis, we suggested that the indole head part would play an important role in improved PPARγ potency. Therefore, while the potent and selective 4-phenly-benzophenone tail was attached to the indole head, compound BPR1H382 (PPARα/γ/δ EC50 = 120/10/>10000 nM), the most potent PPARγ agonist in our study, made stronger H-bonds and hydrophobic interactions with PPARγ than compound BPR1H172 and BPR1H385. The improved activity (EC50) of BPR1H382 was 22-fold potent than the TZD drug, rosiglitazone.

    In summary, through SBDD, the detailed interactions of indole based compounds with protein were elucidated, and guide lead to optimization to obtain the potent PPAR agonists.

    論文摘要................ 2 ABSTRACT 4 誌 謝 6 TABLE OF CONTENTS 7 LIST OF FIGURES 12 LIST OF TABLES 15 ABBREVIATIONS 16 CHAPTER 1 – OVERVIEW AND SPECIFIC AIMS 18 INTRODUCTION 18 TREATMENTS OF TYPE 2 DIABETES 20 Insulin secretagogues 21 Insulin sensitizer – Biguanides and Thiazolidinediones (TZDs) 22 Alpha-Glucosidase inhibitors 24 Incretin effect and a new class of anti-diabetic agent 24 NUCLEAR RECEPTOR: PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS 26 Nuclear receptor superfamily 28 Mechanism of action 28 Structure 30 Mechanism of activation 31 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS) 33 PPARγ 34 PPARα 36 PPARδ 37 PPAR structures 38 Functional domain 39 Crystal structure of PPAR LBD 39 Activation mechanism 42 Heterodimerization with RXR 42 Binding to peroxisome proliferator response element (PPREs) 43 Acitvation by PPAR ligand 46 Natural ligand 46 Synthetic ligand 48 Full agonists 48 Partial agonists 48 Antagonists 49 Ligand binding and coactivators recruitment 52 STRUCTURE BIOLOGY 53 SPECIFIC AIMS 56 CHAPTER 2 - METHOD AND MATERIAL 58 POLYMERASE CHAIN REACTION (PCR) 58 CLONING 59 The clone of pRSETa-PPARγ252-477 59 The clones of pET28a-PPARγ252-477 and pET28a-PPARγ175-477 60 The clones of pGEX6p-1-PPARγ175-477 and pGEX6p-1-PPARγ207-477 60 PROTEIN EXPRESSION AND PURIFICATION 61 Protein of His-PPARγ252-477 61 Protein of GST-PPARγ175-477 62 Protein expression 62 Small-scaled purificaion 62 Large-scaled purification 64 Protein of GST-PPARγLBD207-477 65 Protein expression 65 Cell lysis 65 Large-scaled purification 66 GLUTATHIONE-S-TRANSFERASE (GST) ACTIVITY ASSAY 66 WESTERN BLOT OF ANTI-HIS AND ANTI-PPARΓ 67 PPARγ LBD175-477 68 PPARγ LBD207-477 68 X-RAY DATA COLLECTION AND REFINEMENT 68 ENERGY CALCULATION BY INSIGHTII 69 LIGAND BINDING ASSAY-SCINTILLATION PROXIMITY ASSAY (SPA) 69 CELL CULTURE AND PPAR TRANSACTIVATION (TA) ASSAY 70 RESULT (I) 72 CHAPTER 3 - PROTEIN EXPRESSION, PURIFICATION AND CRYSTALLIZATION 72 INTRODUCTION 74 RESULTS 77 The first clone of His-pRSETa-PPARγ252-477 77 DNA Verification 77 Protein Expression 79 Protein purification 84 The second clone of His-pET28a-PPARγ252-477 86 Protien expression 86 Discussion of His-PPARγ253-477 88 The third clone of GST-PPARγ175-477 89 Preface 90 The Physical property of PPARγ LBD fragments 90 The best protein expression conditions 91 Small-scaled purification of PPARγ175-477 92 Large-scaled purification of PPARγ175-477 94 Protein Verification 97 Crystallization of PPARγ175-477 99 Discussion of GST-PPARγ175-477 102 The fourth clone of GST-PPARγ207-477 103 The best protein expression condition 103 Small-scaled purification of PPARγ207-477 103 Large-scaled protein purification 106 Crystallization, Data collection and structure Determination 109 Discussion of GST-PPARγ207-477 111 CONCLUSION (I) 113 RESULT (II) 116 CHAPTER 4 - A POTENT PPAR PAN AGONIST AS LEAD COMPOUND-BPR1H036 117 INTRODUCTION 117 RESULT 118 Cocrystal structure of PPARγ/BPR1H036 118 Comparisons of other bounded ligands with BPR1H036 in PPARγ 124 Comparisons of overall structure of apo- and BPR1H036-bounded PPARγ LBD 125 DISCUSSION 126 CHAPTER 5 - STRUCTURAL BASED IDENTIFICATION OF A POTENT LINKER BINDING POSITION OF INDOLE BASED PPAR AGONIST DEIGN 127 INTRODUCTION 127 RESULT 129 Cocrystal structure of PPARγ LBD/BPR1H172 129 Comparisons of different linker positions of indole-based agonists 132 DISCUSSION 136 CHAPTER 6 - EFFECT OF A REVERSAL ORIENTATION OF INDOLE HEAD IN PPAR AGONIST DESIGN 137 INTRODUCTION 137 RESULT 139 Comparison of cocrystal structures of BPR1H201 and BPR1H172 139 Comparison of cocrystal structures of BPR1H182 and BPR1H201 142 The proper distance between the acid group and linker 144 DISCUSSION 145 CHAPTER 7 - STRUCTURAL BASED IDENTIFICATION OF A POTENT HYDROPHOBIC TAIL PART BUILDING BLOCK OF INDOLE BASED PPAR AGONIST DESIGN 146 INTRODUCTION 146 RESULT 147 The binding position of analogues with different hydrophobic tail parts in PPARγ LBD 147 Protein-ligand intermolecular energy calculations of agonists with different hydrophobic tail parts 149 Comparison of cocrystal structure of BPR1H378 and BPR1H183 150 PPARγ subtype selectivity of BPR1H378 over PPARα 152 Comparison of cocrystal structure of BPR1H385 with BPR1H378 153 PPARγ subtype selectivity of BPR1H385 over PPARα 156 DISCUSSION 156 CHAPTER 8 - DESIGN THE MOST POTENT PPARΓ AGONIST IN OUR STUDY 159 INTRODUCTION 159 RESULTS 162 Cocrystal structure of BPR1H382 162 Comparison of cocrystal structure of BPR1H382 with BPR1H172 165 Comparison of cocrystal structure of BPR1H382 with BPR1H385 167 Protein-ligand intermolecular energy calculations of PPARγ agonists 170 DISCUSSION 170 CONCLUSION (II) 172 APPENDIX 1 177 APPENDIX 2 191 APPENDIX 3 192 APPENDIX 4 193 APPENDIX 5 195 APPENDIX 6 196 APPENDIX 7 197 APPENDIX 8 198 APPENDIX 9 199 APPENDIX 10 200 REFERENCES 201

    1. Cavaghan MK, Ehrmann DA, Polonsky KS. Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest2000 Aug;106(3):329-33.
    2. Nourparvar A, Bulotta A, Di Mario U, Perfetti R. Novel strategies for the pharmacological management of type 2 diabetes. Trends Pharmacol Sci2004 Feb;25(2):86-91.
    3. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA2002 Jan 16;287(3):360-72.
    4. Hamnvik OP, McMahon GT. Balancing risk and benefit with oral hypoglycemic drugs. Mt Sinai J Med2009 Jun;76(3):234-43.
    5. Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, Wiley C, Selvin E, Wilson R, Bass EB, Brancati FL. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med2007 Sep 18;147(6):386-99.
    6. Kabadi UM, Kabadi M. Comparative efficacy of glimepiride and/or metformin with insulin in type 2 diabetes. Diabetes Res Clin Pract2006 Jun;72(3):265-70.
    7. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T, Vanamo R, Heikkila M. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med1999 Mar 2;130(5):389-96.
    8. Olivera-Gonzalez S, de Escalante-Yanguela B, Velilla-Soriano C, Amores-Arriaga B, Martin-Fortea P, Navarro-Aguilar ME. [Metformin-associated hepatotoxicity.]. Med Intensiva2009 Dec 31.
    9. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med2004 Sep 9;351(11):1106-18.
    10. Campbell IW. The Clinical Significance of PPAR Gamma Agonism. Curr Mol Med2005 May;5(3):349-63.
    11. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med2007 Jun 14;356(24):2457-71.
    12. Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care2000 Nov;23(11):1605-11.
    13. Waites CR, Dominick MA, Sanderson TP, Schilling BE. Nonclinical safety evaluation of muraglitazar, a novel PPARalpha/gamma agonist. Toxicol Sci2007 Nov;100(1):248-58.
    14. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA2005 Nov 23;294(20):2581-6.
    15. Konno S, Tortorelis DG, Fullerton SA, Samadi AA, Hettiarachchi J, Tazaki H. A possible hypoglycaemic effect of maitake mushroom on Type 2 diabetic patients. Diabet Med2001 Dec;18(12):1010.
    16. Pro B, Dang NH. CD26/dipeptidyl peptidase IV and its role in cancer. Histol Histopathol2004 Oct;19(4):1345-51.
    17. Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul Pept2006 Dec 10;137(3):147-55.
    18. Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev2006 Dec;58(4):726-41.
    19. Escriva H, Delaunay F, Laudet V. Ligand binding and nuclear receptor evolution. Bioessays2000 Aug;22(8):717-27.
    20. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell1995 Dec 15;83(6):841-50.
    21. Ricote M, Valledor AF, Glass CK. Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis. Arterioscler Thromb Vasc Biol2004 Feb;24(2):230-9.
    22. Gustafsson JA. Seeking ligands for lonely orphan receptors. Science1999 May 21;284(5418):1285-6.
    23. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade. Cell1995 Dec 15;83(6):835-9.
    24. Bain DL, Heneghan AF, Connaghan-Jones KD, Miura MT. Nuclear receptor structure: implications for function. Annu Rev Physiol2007;69:201-20.
    25. Linja MJ, Porkka KP, Kang Z, Savinainen KJ, Janne OA, Tammela TL, Vessella RL, Palvimo JJ, Visakorpi T. Expression of androgen receptor coregulators in prostate cancer. Clin Cancer Res2004 Feb 1;10(3):1032-40.
    26. Klinge CM, Bodenner DL, Desai D, Niles RM, Traish AM. Binding of type II nuclear receptors and estrogen receptor to full and half-site estrogen response elements in vitro. Nucleic Acids Res1997 May 15;25(10):1903-12.
    27. Novac N, Heinzel T. Nuclear receptors: overview and classification. Curr Drug Targets Inflamm Allergy2004 Dec;3(4):335-46.
    28. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science2001 Nov 30;294(5548):1866-70.
    29. Hu X, Li Y, Lazar MA. Determinants of CoRNR-dependent repression complex assembly on nuclear hormone receptors. Mol Cell Biol2001 Mar;21(5):1747-58.
    30. Guan HP, Ishizuka T, Chui PC, Lehrke M, Lazar MA. Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev2005 Feb 15;19(4):453-61.
    31. Gronemeyer H, Laudet V. Transcription factors 3: nuclear receptors. Protein Profile1995;2(11):1173-308.
    32. Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids1999 May;64(5):310-9.
    33. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature1997 Oct 16;389(6652):753-8.
    34. Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature1995 Jun 1;375(6530):377-82.
    35. Wagner RL, Apriletti JW, McGrath ME, West BL, Baxter JD, Fletterick RJ. A structural role for hormone in the thyroid hormone receptor. Nature1995 Dec 14;378(6558):690-7.
    36. Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev2000 Jan 15;14(2):121-41.
    37. Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM. Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell1999 Sep 3;98(5):675-86.
    38. Manteuffel-Cymborowska M. Nuclear receptors, their coactivators and modulation of transcription. Acta Biochim Pol1999;46(1):77-89.
    39. Rosen ED, Spiegelman BM. PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem2001 Oct 12;276(41):37731-4.
    40. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta1996 Jul 26;1302(2):93-109.
    41. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem2000 Feb 24;43(4):527-50.
    42. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell1995 Dec 1;83(5):803-12.
    43. Willson TM, Wahli W. Peroxisome proliferator-activated receptor agonists. Curr Opin Chem Biol1997 Aug;1(2):235-41.
    44. Wahli W, Braissant O, Desvergne B. Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more. Chem Biol1995 May;2(5):261-6.
    45. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem1995 Jun 2;270(22):12953-6.
    46. Tontonoz P, Hu E, Spiegelman BM. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. Curr Opin Genet Dev1995 Oct;5(5):571-6.
    47. Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP, Staels B, Auwerx J, Laville M, Vidal H. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes1997 Aug;46(8):1319-27.
    48. Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem1997 Jul 25;272(30):18779-89.
    49. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem2001;70:341-67.
    50. Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, Caro JF, Flier JS. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest1997 May 15;99(10):2416-22.
    51. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell1994 Dec 30;79(7):1147-56.
    52. Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci2005 May;26(5):244-51.
    53. Laplante M, Sell H, MacNaul KL, Richard D, Berger JP, Deshaies Y. PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion. Diabetes2003 Feb;52(2):291-9.
    54. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest2003 Dec;112(12):1821-30.
    55. Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ, Hotamisligil GS, Spiegelman BM. Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology1994 Jan;134(1):264-70.
    56. Miles PD, Romeo OM, Higo K, Cohen A, Rafaat K, Olefsky JM. TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes1997 Nov;46(11):1678-83.
    57. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology1996 Jan;137(1):354-66.
    58. Linton MF, Fazio S. Re-emergence of fibrates in the management of dyslipidemia and cardiovascular risk. Curr Atheroscler Rep2000 Jan;2(1):29-35.
    59. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med2002;53:409-35.
    60. Inoue I, Shino K, Noji S, Awata T, Katayama S. Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. Biochem Biophys Res Commun1998 May 19;246(2):370-4.
    61. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem1999 Nov 5;274(45):32048-54.
    62. Oliver WR, Jr., Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A2001 Apr 24;98(9):5306-11.
    63. Graham TL, Mookherjee C, Suckling KE, Palmer CN, Patel L. The PPARdelta agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice. Atherosclerosis2005 Jul;181(1):29-37.
    64. Leibowitz MD, Fievet C, Hennuyer N, Peinado-Onsurbe J, Duez H, Bergera J, Cullinan CA, Sparrow CP, Baffic J, Berger GD, Santini C, Marquis RW, Tolman RL, Smith RG, Moller DE, Auwerx J. Activation of PPARdelta alters lipid metabolism in db/db mice. FEBS Lett2000 May 19;473(3):333-6.
    65. Kang K, Hatano B, Lee CH. PPAR delta agonists and metabolic diseases. Curr Atheroscler Rep2007 Jan;9(1):72-7.
    66. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature1992 Aug 27;358(6389):771-4.
    67. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature1998 Sep 10;395(6698):137-43.
    68. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell1999 Mar;3(3):397-403.
    69. Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT, Jr., McKee DD, Moore JT, Willson TM. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A2001 Nov 20;98(24):13919-24.
    70. Miyata KS, McCaw SE, Marcus SL, Rachubinski RA, Capone JP. The peroxisome proliferator-activated receptor interacts with the retinoid X receptor in vivo. Gene1994 Oct 21;148(2):327-30.
    71. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, Evans RM. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev1992 Mar;6(3):329-44.
    72. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. Structure of the intact PPAR-gamma-RXR-alpha nuclear receptor complex on DNA. Nature2008 Oct 29:350-6.
    73. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature2008 Nov 20;456(7220):350-6.
    74. Krey G, Keller H, Mahfoudi A, Medin J, Ozato K, Dreyer C, Wahli W. Xenopus peroxisome proliferator activated receptors: genomic organization, response element recognition, heterodimer formation with retinoid X receptor and activation by fatty acids. J Steroid Biochem Mol Biol1993 Dec;47(1-6):65-73.
    75. A IJ, Jeannin E, Wahli W, Desvergne B. Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA. A functional analysis of the malic enzyme gene PPAR response element. J Biol Chem1997 Aug 8;272(32):20108-17.
    76. Issemann I, Prince RA, Tugwood JD, Green S. The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J Mol Endocrinol1993 Aug;11(1):37-47.
    77. Gearing KL, Gottlicher M, Teboul M, Widmark E, Gustafsson JA. Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc Natl Acad Sci U S A1993 Feb 15;90(4):1440-4.
    78. Lin CH, Peng YH, Coumar MS, Chittimalla SK, Liao CC, Lyn PC, Huang CC, Lien TW, Lin WH, Hsu JT, Cheng JH, Chen X, Wu JS, Chao YS, Lee HJ, Juo CG, Wu SY, Hsieh HP. Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists. J Med Chem2009 Apr 23;52(8):2618-22.
    79. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell1995 Dec 1;83(5):813-9.
    80. Powell WS. 15-Deoxy-delta12,14-PGJ2: endogenous PPARgamma ligand or minor eicosanoid degradation product? J Clin Invest2003 Sep;112(6):828-30.
    81. Itoh T, Fairall L, Amin K, Inaba Y, Szanto A, Balint BL, Nagy L, Yamamoto K, Schwabe JW. Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat Struct Mol Biol2008 Sep;15(9):924-31.
    82. Nettles KW, Greene GL. Ligand control of coregulator recruitment to nuclear receptors. Annu Rev Physiol2005;67:309-33.
    83. Nagy L, Schwabe JW. Mechanism of the nuclear receptor molecular switch. Trends Biochem Sci2004 Jun;29(6):317-24.
    84. Bruning JB, Chalmers MJ, Prasad S, Busby SA, Kamenecka TM, He Y, Nettles KW, Griffin PR. Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure2007 Oct;15(10):1258-71.
    85. Kallenberger BC, Love JD, Chatterjee VK, Schwabe JW. A dynamic mechanism of nuclear receptor activation and its perturbation in a human disease. Nat Struct Biol2003 Feb;10(2):136-40.
    86. Pochetti G, Godio C, Mitro N, Caruso D, Galmozzi A, Scurati S, Loiodice F, Fracchiolla G, Tortorella P, Laghezza A, Lavecchia A, Novellino E, Mazza F, Crestani M. Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands. J Biol Chem2007 Jun 8;282(23):17314-24.
    87. Bendixen AC, Shevde NK, Dienger KM, Willson TM, Funk CD, Pike JW. IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1. Proc Natl Acad Sci U S A2001 Feb 27;98(5):2443-8.
    88. Lu IL, Huang CF, Peng YH, Lin YT, Hsieh HP, Chen CT, Lien TW, Lee HJ, Mahindroo N, Prakash E, Yueh A, Chen HY, Goparaju CM, Chen X, Liao CC, Chao YS, Hsu JT, Wu SY. Structure-based drug design of a novel family of PPARgamma partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities. J Med Chem2006 May 4;49(9):2703-12.
    89. Oberkofler H, Esterbauer H, Linnemayr V, Strosberg AD, Krempler F, Patsch W. Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 recruitment regulates PPAR subtype specificity. J Biol Chem2002 May 10;277(19):16750-7.
    90. Pissios P, Tzameli I, Kushner P, Moore DD. Dynamic stabilization of nuclear receptor ligand binding domains by hormone or corepressor binding. Mol Cell2000 Aug;6(2):245-53.
    91. Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature1997 Jun 12;387(6634):733-6.
    92. Otwinowski Z, Minor W. Processing of X-ray Diffraction Data Collected in Oscillation Mode. Methods in Enzymology1997. p. 307- 26.
    93. Vagin A, Teplyakov A. MOLREP: an automated program for molecular replacement. J Appl Crystallogr1997;30:1022 -5.
    94. Murshudov GN, Vagin AA, Dodson EJ. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr1997 May 1;53(Pt 3):240-55.
    95. Jones TA, Zou JY, Cowan SW, Kjeldgaard M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A1991 Mar 1;47 ( Pt 2):110-9.
    96. Joosten RP, Vriend G. PDB improvement starts with data deposition. Science2007 Jul 13;317(5835):195-6.
    97. Mahindroo N, Huang CF, Peng YH, Wang CC, Liao CC, Lien TW, Chittimalla SK, Huang WJ, Chai CH, Prakash E, Chen CP, Hsu TA, Peng CH, Lu IL, Lee LH, Chang YW, Chen WC, Chou YC, Chen CT, Goparaju CM, Chen YS, Lan SJ, Yu MC, Chen X, Chao YS, Wu SY, Hsieh HP. Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities. J Med Chem2005 Dec 29;48(26):8194-208.
    98. Holt JA, Consler TG, Williams SP, Ayscue AH, Leesnitzer LM, Wisely GB, Billin AN. Helix 1/8 interactions influence the activity of nuclear receptor ligand-binding domains. Mol Endocrinol2003 Sep;17(9):1704-14.
    99. Santini C, Berger GD, Han W, Mosley R, MacNaul K, Berger J, Doebber T, Wu M, Moller DE, Tolman RL, Sahoo SP. Phenylacetic acid derivatives as hPPAR agonists. Bioorg Med Chem Lett2003 Apr 7;13(7):1277-80.
    100. Ebdrup S, Pettersson I, Rasmussen HB, Deussen HJ, Frost Jensen A, Mortensen SB, Fleckner J, Pridal L, Nygaard L, Sauerberg P. Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar. J Med Chem2003 Apr 10;46(8):1306-17.
    101. GOLD. CCDC software Limited,Cambridge, UK; 2004.
    102. Mahindroo N, Wang CC, Liao CC, Huang CF, Lu IL, Lien TW, Peng YH, Huang WJ, Lin YT, Hsu MC, Lin CH, Tsai CH, Hsu JT, Chen X, Lyu PC, Chao YS, Wu SY, Hsieh HP. Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: design, synthesis, structural biology, and molecular docking studies. J Med Chem2006 Feb 9;49(3):1212-6.

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