Abstract
A QSAR study on a series of indanylacetic acid derivatives with activity against PPAR-α, δ, and γ was made using combination of various physiochemical descriptors. Several statistical regression expressions were obtained using stepwise multiple linear regression (MLR) analysis and partial least square (PLS) method. The highly predictive and validated models generated through classical 2D molecular descriptors provided deeper insights about the binding of these small molecules to the human nuclear receptor PPAR-α, δ, and γ. The results reveal that dipole moment and number of hydrogen bond donors are important descriptors in determining effective binding of PPAR agonists to all three subtypes.
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Artis DR, Lin JJ, Zhang C, Wang W, Mehra U, Perreault M, Erbe D, Krupka HI, England BP, Arnold J (2009) Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci USA 106:262–267
Auwerx J (1999) PPAR γ, the ultimate thrifty gene. Diabetologia 42:1033–1049
Balfour B, Plosker GL (1999) Rosiglitazone. Drugs 57:921–930
Barish GD, Narkar VA, Evans RM (2006) PPAR δ: a dagger in the heart of the metabolic syndrome. J Clin Investig 116:590–597
Besalu E (2007) Trends and plot methods in MLR studies. J Chem Inf Model 47:751–760
Cheng CF, Chen HH, Lin H (2010) Role of PPARα and its agonist in renal diseases. PPAR Res. doi:10.1155/2010/345098
Cramer RD (1993) Partial Least Square (PLS): its strength and limitations. Perspect Drug Discov Des 1:269–278
Cronin MTD, Schultz TW (2001) Development of quantitative structure–activity relationships for the toxicity of aromatic compounds to Tetrahymena pyriformis: comparative assessment of the methodologies. Chem Res Toxicol 14:1284–1295
Dalby A, Nourse JG, Hounshell WD, Gushurst AKI, Grier DL, Leland BA, Laufer J (1992) Description of several chemical structure file formats used by computer programs developed at Molecular Design Limited. J Chem Inf Comput Sci 32:244–255
Dessalew N (2008) QSAR study on piperidine carboxamides as antiretroviral agents: an insight into the structural basis for HIV coreceptor antagonist activity. QSAR Comb Sci 27:901–912
Dessalew N (2009) Investigation of the structural requirement for inhibiting HIV integrase: QSAR study. Acta Pharm 59:31–43
Ebdrup S, Petterson I, Rasmussen HB, Deussen HJ, Frost JA, Mortensen SB, Fleckner J, Pridal L, Nygaard L, Sauerberg P (2003) Synthesis and biological and structural characterization of the dual acting peroxisome proliferator-activated receptor α/γ agonist Ragaglitazar. J Med Chem 46:1306–1317
Fagerberg B, Edwards S, Halmos T, Lopatynski J, Schuster H (2005) Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 48:1716–1725
Furusjö E, Svenson A, Rahmberg M, Andersson M (2006) The importance of outlier detection and training set selection for reliable environmental QSAR predictions. Chemosphere 63:99–108
Hall LH, Mohney BK, Kier LB (1991) The electrotopological state: an atom index for QSAR. Quant Struct Act Relat 10:43–51
Hanch C, Muir RM, Fujita T, Maloney P, Geiger E, Streich M (1963) Correlation of biological activity of plant growth regulators and chloromycetin derivatives with Hammett constants and partition coefficient. J Am Chem Soc 85:2817–2824
Hawkins DM, Basak SC, Mills D (2003) Assessing model fit by cross-validation. J Chem Inf Comput Sci 43:579–586
Hendrickson MA, Nicklaus MC, Milne GWA, Zaharevitz D (1993) D.CONCORD and CAMBRIDGE: comparison of computer-generated chemical structures with X-ray crystallographic data. J Chem Inf Comput Sci 33:155
Henke BR (2004) Peroxisome proliferators-activated receptor α/γ dual agonists for the treatment of type 2 diabetes. J Med Chem 47:4118–4127
Karelson M (2000) Molecular descriptors in QSAR/QSPR. Wiley Interscience, New York, pp 220–221
Kordik CP, Reitz AB (1999) Pharmacological treatment of obesity: therapeutic strategies. J Med Chem 42:181–201
Kovatcheva A, Buchbauer G, Golbraikh A, Wolschann P (2003) QSAR modeling of r-campholenic derivatives with sandalwood odor. J Chem Inf Comput Sci 43:259–266
Lin Y, Sun Z (2010) Current views on type 2 diabetes. J Endocrinol 204:1–11. doi:10.1677/JOE-09-0260
Lin Q, Ruuska SE, Shaw NS, Dong D, Noy N (1999) Ligand selectivity of the peroxisome proliferator-activated receptor α. Biochemistry 38:185–190
Liu K, Xu L, Berger JP, MacNaul KL, Zhou G, Doebber TWM, Forrest J (2005) Discovery of a novel series of peroxisome proliferator-activated receptor α/γ dual agonists for the treatment of type 2 diabetes and dyslipidemia. J Med Chem 48:2262–2265
Luco JM, Ferretti FH (1997) QSAR based on multiple linear regression and partial least square methods for the anti-HIV activity of a large group of HEPT derivatives. J Chem Inf Comput Sci 37:392–401
Markt P, Schuster D, Kirchmair J, Laggner C, Langer T (2007) Pharmacophore modeling and parallel screening for PPAR ligands. J Comput Aided Mol Des 21:575–590. doi:10.1007/s10822-007-9140-0
Mudaliar S, Hery RR (2002) PPAR agonists in health and disease: pathophysiologic and clinical overview. Curr Opin Endocrinol Diabetes 9:285–302
Paliwal S, Narayan A, Paliwal S (2009) Quantitative structure activity relationship analysis of dicationic diphenylisoxazole as potent anti-trypanosomal agents. QSAR Comb Sci 28:1367–1375
Paliwal SK, Pal M, Siddiqui AA (2010a) Quantitative structure activity relationship analysis of angiotensin II AT1 receptor antagonist. Med Chem Res 19:475–489
Paliwal SK, Singh S, Kumari S, Siddiqui AA, Paliwal SK (2010b) QSAR studies of imidazo [1,5a]quinoxalines amides, carbamates and urea as potent GABA modulators. Indian J Chem B 49B:554–560
Paliwal SK, Das S, Yadav D, Saxena M, Paliwal SK (2010c) Quantitative structure activity relationship (QSAR) of N 6-substituted adenosine receptor agonists as potential antihypertensive agents. Med Chem Res. doi:10.1007/s00044-010-9478-z
Paliwal S, Seth D, Yadav D, Paliwal S, Yadav R (2011) Development of a robust QSAR model to predict the affinity of pyrrolidine analogs for dipeptidyl peptidase IV (DPP-IV). J Enzym Inhib 26:129–140. doi:10.3109/14756361003777057
Prasad YR, Kumar PR, Smiles DJ, Babu PA (2008) QSAR studies on chalcone derivatives as antibacterial agents against Bacillus pumilis. Arkivoc 11:266–276
Rameshwar N, Krishna K, Kumar BA, Parthasarathy T (2006) QSAR studies of N 1-(5-chloro-2-pyridyl)-2-{[4-(alkylmethyl)benzoyl]amino}-5-chlorobenzamide analogs. Bioorg Med Chem 14:319–325
Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM (1999) PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4:611–617. doi:10.1016/S1097-2765(00)80211-7
Rudolph J, Chen L, Majumdar D, Bullock WH, Burns M, Claus T, Dela Cruz FE, Daly M, Ehrgott FJ, Johnson JS, Livingston JN, Schoenleber RW, Shapiro J, Yang L, Tsutsumi M, Ma X (2007) Indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups, a new class of potent PPAR α/δ/γ pan agonists: synthesis, structure–activity relationship, and in vivo efficacy. J Med Chem 50:984–1000
Sadowski J, Gasteiger J (1993) From atoms and bonds to three-dimensional atomic coordinates: automatic model builders. Chem Rev 93:2567–2581
Takahashi M, Eto M, Makino I (1993) Peripheral insulin resistance precedes the onset of hyperglycemia in spontaneously diabetic Chinese hamsters of Asahikawa colony. Diabetes Res Clin Pract 20:101–109
Tarko L, Ivanciuc O (2001) QSAR modeling of the anticonvulsant activity of phenylacetanilides with preclav (property evaluation by class variables). Match Commun Math Comput Chem 44:201–214
Tenenbaum A, Motro M, Fisman EZ (2005) Dual and pan—peroxisome proliferators-activator receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovasc Diabetol 4:14
Todeschini R, Consonni V (2000) Handbook of molecular descriptors: methods and principles in medicinal chemistry. Wiley-VCH, Weinheim
Topliss JG (1993) Some observation on classical QSAR. Perspect Drug Discov Des 1:253–268
Wang M, Ross SA, Gulve EA (2004) Chemistry and biochemistry of type 2 diabetes. Chem Rev 104:1255–1282
Willson TM, Brown PJ, Sternbach DD, Henke BR (2000) The PPARs: from orphan receptors to drug discovery. J Med Chem 43:527–550
Wold S (2001) PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst 58:109–130
Wylie WA, Vinter JG (1994) In: Gardner M (ed) Molecular modeling and drug design. Macmillan, London
Yanase T, Yashiro T, Takitani K, Kato S, Taniguchi S, Takayanagi R, Nawata H (1997) Differential expression of PPAR γ1 and γ2 isoforms in human adipose tissue. Biochem Biophys Res Commun 233:320–324. doi:10.1006/bbrc.1997.6446
Zoete V, Grosdidier A, Michielin O (2007) Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta Mol Cell Biol Lipid 1771:915–925. doi:10.1016/j.bbalip.2007.01.007
Acknowledgment
The computational resources were provided by Banasthali University, and the authors thank the Vice Chancellor, for extending the necessary facilities.
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The authors report no conflict of interest. The authors alone are responsible for the contents and writing of the paper.
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Paliwal, S., Yadav, D., Yadav, R. et al. Common binding requirements of PPAR-α/δ/γ pan agonists: quantitative structure–activity relationship analysis of indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail group. Med Chem Res 21, 891–907 (2012). https://doi.org/10.1007/s00044-011-9599-z
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DOI: https://doi.org/10.1007/s00044-011-9599-z