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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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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The author thanks Vlife Science Technologies Pvt. Ltd for providing the trial version software for the study.
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- Ferreira MMC (2002) Multivariate QSARh. J. Braz. Chem. Soc., 13, 742–753.Google Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- Leach AR, Gillet VJ (2003) An Introduction to Chemoinformatics. Kluwer, Boston, pp 79–81.Google Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar
- 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
- VLife MDS 3.5 (2008) Molecular design suite. Vlife SciencesTechnologies Pvt. Ltd., Pune.Google Scholar
- World Health Organization, Fact Sheet No. 138, April 2002.Google Scholar
- 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.CrossRefGoogle Scholar