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Prospective QSAR-based Prediction Models with Pharmacophore Studies of Oxadiazole-substituted α-isopropoxy Phenylpropanoic Acids on with Dual Activators of PPARα and PPARγ

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Abstract

A series of oxadiazole-substituted α-isopropoxy phenylpropanoic acids with dual activators of PPARα and PPARγ derivatives were subjected to two dimensional and k-nearest neighbour Molecular field analysis. The statistically significant best 2D-QSAR (PPARα) model having good predictive ability with statistical values of r2 = 0.8725, q2 = 0.7957 and pred_r2 = 0.8136, was developed by GA-PLS with the descriptors like SsClcount, SddsN (nitro) count and SsOHcount contribute significantly to the biological activity. The best 3D-QSAR studies (PPARα) were performed using the genetic algorithm selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2=0.7188 and predicate activity pred_r2 = 0.7508 were obtained. The influences of steric and electrostatic field effects generated by the contribution plots are discussed. The best pharmacophore model includes three features viz. hydrogen bond donor, hydrogen bond acceptor, and aromatic features were developed. The information rendered by 2D, 3D QSAR models may lead to a better understanding of structural requirements of substituted α-isopropoxy phenylpropanoic derivatives and also aid in designing novel potent PPARα and PPARγ for antihyperglycemic molecules.

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References

  1. Amos AF, McCarty DJ, Zimmet P (1997) The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 14(5): S1–85

    PubMed  Google Scholar 

  2. Ajmani S, Jadhav K, Kulkarni SA (2006) Three-Dimensional QSAR using the k-Nearest Neighbor method and its interpretation. J Chem Inf Model 46: 24–31.

    Article  CAS  Google Scholar 

  3. Baumann K (2000) an alignment-independent versatile structure descriptor for QSAR and QSPR based on the distribution of molecular features. J Chem Inf Comput Sci 42: 26–35.

    Article  Google Scholar 

  4. Basu-Modak S, Braissant O, Escher P, Desvergne B, Honegger P, Wahli W (1999) Peroxisome Proliferator- Activated Receptor β Regulates Acyl-CoA Synthetase 2 in Reaggregated Rat Brain Cell Cultures. J Biol Chem 274: 35881-35888.

    Article  CAS  Google Scholar 

  5. Berger J, Bailey P, Biswas C, Cullinan C A, Doebber TW, Hayes N S, Saperstein R, Smith R G, Leibowitz MD (1996) Thiozolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-γ: binding and activation correlates with antidiabetic actions in db/db mice. Endocrinology 137: 4189–4195.

    Article  CAS  Google Scholar 

  6. Brun RP, Kim JB, Hu E, Spiegelman BM (1997) Peroxisome proliferator-activated receptor gamma and the control of adipogenesis. Curr Opin Lipidol 8(4): 212–8.

    Article  CAS  Google Scholar 

  7. Buckle DR, Cantello BCC, Cawthorne M A, Coyle P J, Dean D K, Faller A, Haigh D, Hindley R M, Jefcott L J, Lister C A, Pinto I L, Rami H K, Smith D G, Smith S A (1996) Nonthiazolidinedione Antihyperglycemic Agents. 1: α-Heteroatom Substituted β-Phenylpropanoic Acids. Bioorg Med Chem Lett 6: 2121–2126.

    Article  CAS  Google Scholar 

  8. Bhatia MS, Pakhare KD, Choudhari PB, Jadhav S D, Dhavale, RP, Bhatia NM (2012) Pharmacophore modeling and 3D QSAR studies of aryl amine derivatives as potential lumazine synthase inhibitors. Arab J Chem https://doi.org/10.1016/j.arabjc.2012.05.008.

    Google Scholar 

  9. Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA) 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110: 5959–5967.

    Article  CAS  Google Scholar 

  10. Clark M, Cramer RD III, Van ON (1989) Validation of the general purpose tripos 5.2 force field. J Comput Chem 10: 982–1012.

    Article  CAS  Google Scholar 

  11. Choudhari P, Bhatia M (2012) 3D QSAR, pharmacophore indentification studies on series of 1- (2-ethoxyethyl)-1Hpyrazolo [4, 3-d] pyrimidines as phosphodiesterase V inhibitors. J Saudi Chem Soc https://doi.org/10.1016/j.jscs.2012.02.008.

    Google Scholar 

  12. Collins J L, Blanchard SG, Boswell EG, Charifson PS, Cobb JE, Henke B R, Hull-Ryde E A, Kazmierski W W, Lake DH, Leesnitzer L M, Lehmann J, Lenhard J M, Orband-Miller L A, Gray-Nunez Y, Parks D J, Plunket KD, Tong, W (1998) N-(2-Benzoylphenyl)-Ltyrosine PPAR-Cc Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety. J Med Chem 41: 5037–5054.

    Article  CAS  Google Scholar 

  13. Dow R L, Bechle BM, Chou T T, Clark DA, Hulin B, Stevenson RW (1991) Benzyloxazolidine-2, 4-dines as Potent Hypoglycemic Agents. J Med Chem 34: 1538–1554.

    Article  CAS  Google Scholar 

  14. Diamant M, Heine RJ (2003) Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs 63(13): 1373–405.

    Article  CAS  Google Scholar 

  15. Ferreira MMC (2002) Multivariate QSARh. J. Braz. Chem. Soc., 13, 742–753.

    CAS  Google Scholar 

  16. Gross B, Staels B (2007) PPAR agonists: multimodal drugs for the treatment of type-2 diabetes. Best Pract Res Clin Endo crinol Meta 21(4): 687–710.

    Article  CAS  Google Scholar 

  17. Golbraikh A, Tropsha A (2002) Predictive QSAR modeling based on diversity sampling of experimental datasets for the training and test set selection. J Comput Aided Mol Des 16: 357–369.

    Article  CAS  Google Scholar 

  18. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron 36: 3219–3228.

    Article  CAS  Google Scholar 

  19. Hasegawa K, Kimura T, Funatsu K (1999) GA Strategy for Variable Selection in QSAR Studies: Enhancement of Comparative Molecular Binding Energy Analysis by GA-Based PLS Method. Quant Struct Act Relat 18: 262–272.

    Article  CAS  Google Scholar 

  20. Henke B R (2004) Proxisome Proliferators-Activated Receptor α/γ Dual Agonists for the Treatment of Type 2 Diabetes. J Med Chem 47, 4118–4127.

    Article  CAS  Google Scholar 

  21. Holland J H (1992) Genetic algorithms. Sci Am 267: 66–72.

    Article  Google Scholar 

  22. Halgren TA (1996) Merck molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94. J Comput Chem 17: 553–586.

    Article  CAS  Google Scholar 

  23. Jönsson B (2002) Revealing the cost of Type II diabetes in Europe. Diabetologia 45, S5–12.

    Article  Google Scholar 

  24. Joy SV, Rodgers PT, Scates AC (2005) Incretinmimetics as emerging treatments for type 2 diabetes. Ann Pharmacother 39, 110–118.

    Article  CAS  Google Scholar 

  25. Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, Hickey GJ, Kowalchick JE, Leiting B, Lyons K, Marsilio F, McCann ME, Patel RA, Petrov A, Scapin G, Patel SB, Roy RS, Wu JK, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE (2005) (2R)-4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro[1, 2, 4]triazolo[4, 3- a]pyrazin-7(8H)-yl]-1-(2, 4, 5 trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48: 141–151.

    Article  CAS  Google Scholar 

  26. Kersten S, Desvergne B, Wahli W (2000) Roles of PPARs in health and disease. Nature 405, 421–424.

    Article  CAS  Google Scholar 

  27. King H, Aubert RE, Herman WH (1998) Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes. Care 21: 1414–1431.

    Article  CAS  Google Scholar 

  28. Liu KG, Smith JS, Ayscue AH, Henke BR, Lambert MH, Leesnitzer LM, Plunket KD, Willson TM, Sternbach DD (2001) Identification of a series of oxadiazolesubstituted alpha-isopropoxyphenylpropanoic acids with activity on PPARα, PPARγ, and PPARδ. Bioorg Med Chem Lett 11: 2385–2388.

    Article  CAS  Google Scholar 

  29. Lemberger T, Desvergne B, Wahli W (1996) Peroxisome Proliferator-Activated Receptors: A Nuclear Receptor Signaling Pathway in Lipid Physiology. Annu Rev Cell Dev Biol 12: 335–363.

    Article  CAS  Google Scholar 

  30. 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 (1999) (-)3- [4-[2-(Phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic Acid [(-)DRF 2725]: A Dual PPAR Agonist with Potent Antihyperglycemic and Lipid Modulating Activity. J Med Chem 42: 2569–2581.

    Article  CAS  Google Scholar 

  31. Leach AR, Gillet VJ (2003) An Introduction to Chemoinformatics. Kluwer, Boston, pp 79–81.

    Google Scholar 

  32. Lehmann J M, Moore LB, Smith-Oliver T A, Wilkison WO, Willson TM, Kliewer S A (1995) An Antidiabetic Thiazolidinedione is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor γ (PPAR γ). J Biol Chem 270: 12953–12956.

    Article  CAS  Google Scholar 

  33. Mangelsdorf DJ, Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83: 841–50.

    Article  CAS  Google Scholar 

  34. Murakami K, Tobe K, Ide T, Mochizuki T, Ohashi M, Akanuma Y, Yazaki Y, Kadowaki T (1998) A novel insulin sensitizer acts as a colig and for peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 47: 1841–7.

    Article  CAS  Google Scholar 

  35. Momose Y, Maekawa T, Yamano T, Kawada M, Odaka H, Ikeda H, Sohda T (2002) Novel 5-Substituted 2, 4-Thiazolidinedione and 2, 4-Oxazolidinedione Derivatives as Insulin Sensitizers with Antidiabetic Activities. J Med Chem 45: 1518–1534.

    Article  CAS  Google Scholar 

  36. Nissen S E, Wolski K, Topol E J (2005) Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. J Am Med Assoc 294: 2581–2586.

    Article  CAS  Google Scholar 

  37. Oberfield J L, Collins J L, Holmes C P, Goreham D M, Cooper J P, Cobb J E, Lenhard J M, Hull-Ryde EA, Mohr C P, Blanchard S G, Parks D J, Moore L B, Lehmann JM, Plunket K, Miller A B, Milburn MV, Kliewer S AM., Kliewer WT (1999) A peroxisome proliferatoractivated receptor γ ligand inhibits adipocyte differentiation. Proc Nat Aca Sc 96: 6102–6106.

    Article  CAS  Google Scholar 

  38. Oliver W R Jr, Shenk J L, Snaith M R, Russell C S, Plunket K D, Bodkin N L, Lewis M C, Winegar DA, Sznaidman ML, Lambert M H, Xu H E, Sternbach D D, Kliewer S A, Hansen B C, Willson T M (2001) A Selective Peroxisome Proliferator- Activated Receptor δ Agonist Promotes Reverse Cholesterol Transport. Proc Natl Acad Sci USA 98: 5306–5311.

    Article  CAS  Google Scholar 

  39. Park BH, Vogelstein B, Kinzler K W (2001) Genetic Disruption of PPAR Decreases the Tumorigenicity of Human Colon Cancer Cells. Proc Natl Acad Sci USA 98: 2598–2603.

    Article  CAS  Google Scholar 

  40. Ram VJ (2003) Therapeutic role of peroxisome proliferator-activated receptors in obesity, diabetes and inflammation. Prog Drug Res 60: 93–132.

    Article  CAS  Google Scholar 

  41. 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 S, Mortensen S B, Svensson L A, Rasmussen H B, Lehmann S V, Polivka Z, Sindelar K, Panajotova V, Ynddal L, Wulff E M (2002) Novel tricyclic-alpha alkyloxyphenylpropionic acids: dual PPARα/γ agonists with hypolipidemic and antidiabetic activity. J Med Chem 45: 789–804.

    Article  CAS  Google Scholar 

  42. Sotriffer CA, Winger RH, Liedl KR, Rode BM, Varga JM., 1996. Comparative docking studies on ligand binding to the multispecific antibodies IgE-La2 and IgE-Lb4. J Comput Aided Mol Des 10(4): 305–20.

    Article  CAS  Google Scholar 

  43. Sohda T K M, Imamiya E, Sugiyama Y, Fujita T, Kawamatsu Y (1982) Studies on Antidiabetic Agents. II. Syhthesis of 5-[4-(1- Methylcyclohexylmethoxybenzyl]thiazolidine-2, 4-dione (ADD-3878) and Its Derivatives. Chem Pharm Bull 3580–3600.

    Google Scholar 

  44. Shinkai H, Onogi S, Tanaka M, Shibata T, Iwao M, Wakitani K, Uchida I (1998) Isoxazolidine-3, 5-dione and Noncyclic1, 3-Dicarbonyl Compounds as Hypoglycemic Agents. J Med Chem 41: 1927–1933.

    Article  CAS  Google Scholar 

  45. Spiegelman BM (1998) PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 47: 507–514.

    Article  CAS  Google Scholar 

  46. Smith A, Fogelfeld L, Bakris G (2000). New therapies in diabetes - thiazolidinediones. Emerg Drugs 5: 441–456.

    Article  CAS  Google Scholar 

  47. Shearer B G, Billin A N (2007) The next generation of PPAR drugs: do we have the tools to find them? Biochim Biophys Acta 1771: 1082–93.

    Article  CAS  Google Scholar 

  48. Staels B, Fruchart J C (2005) Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 54: 2460–70.

    Article  CAS  Google Scholar 

  49. VLife MDS 3.5 (2008) Molecular design suite. Vlife SciencesTechnologies Pvt. Ltd., Pune.

    Google Scholar 

  50. World Health Organization, Fact Sheet No. 138, April 2002.

    Google Scholar 

  51. Willson T M, Cobb J E, Cowan D J, Wiethe R W, Corea I D, Prakash SR Beck K D, Moore L B, Kliver S A, Lehman J M (1996) The structure-activity relationship between peroxisome proliferator-activatied receptor γ agonism and the antihyperglycemic activity of thiozolidinediones. J Med Chem 39: 665–668.

    Article  CAS  Google Scholar 

  52. Wagman AS, Nuss JM. 2001. Current therapies and emerging targets for the treatment of diabetes. Curr. Pharm. Des. 7: 417–50.

    Article  CAS  Google Scholar 

  53. Wang Y X, Zhang C L, Yu R T, Cho H K, Nelson M C, Bayuga-Ocampo C R, Ham J, Kang H, Evans RM (2004) Regulation of Muscle Fiber Type and Running Endurance by PPARδ. PLoS Biol 2: E294.

    Article  Google Scholar 

  54. Zheng W, Tropsha A (2000) Novel variable selection quantitative structure-property relationship approach based on the k-nearest neighbor principle. J Chem Inf Comput Sci 40: 185–194.

    Article  CAS  Google Scholar 

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Acknowledgment

The author thanks Vlife Science Technologies Pvt. Ltd for providing the trial version software for the study.

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  1. Drug Design and Development Laboratory, School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshila Campus, Khandwa Road, Indore (M.P), 452 001, India

    Mukesh C. Sharma

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Sharma, M.C. Prospective QSAR-based Prediction Models with Pharmacophore Studies of Oxadiazole-substituted α-isopropoxy Phenylpropanoic Acids on with Dual Activators of PPARα and PPARγ. Interdiscip Sci Comput Life Sci 7, 335–346 (2015). https://doi.org/10.1007/s12539-015-0009-y

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