Structural Insights for the Design of New PPARgamma Partial Agonists with High Binding Affinity and Low Transactivation Activity

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2011 Jun 22

PMID 21691811

Citations 13

Authors

Laura Guasch

Esther Sala

Cristina Valls

Mayte Blay

Miquel Mulero

Lluis Arola

Gerard Pujadas

Santiago Garcia-Vallve

Affiliations

Soon will be listed here.

Abstract

Peroxisome Proliferator-Activated Receptor γ (PPARγ) full agonists are molecules with powerful insulin-sensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds also present various side effects. Recent results suggest that effective PPARγ agonists should show a low transactivation activity but a high binding affinity to inhibit phosphorylation at Ser273. We use several structure activity relationship studies of synthetic PPARγ agonists to explore the different binding features of full and partial PPARγ agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARγ. Our results suggest that effective partial agonists should have a hydrophobic moiety and an acceptor site with an appropriate conformation to interact with arm II and establish a hydrogen bond with Ser342 or an equivalent residue at arm III. Despite the fact that interactions with arm I increase the binding affinity, this region should be avoided in order to not increase the transactivation activity of potential PPARγ partial agonists.

Citing Articles

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References

Bruning J, Chalmers M, Prasad S, Busby S, Kamenecka T, He Y . Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure. 2007; 15(10):1258-71. DOI: 10.1016/j.str.2007.07.014. View

Lu I, Huang C, Peng Y, Lin Y, Hsieh H, Chen C . 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 Chem. 2006; 49(9):2703-12. DOI: 10.1021/jm051129s. View

Willson T, Lambert M, Kliewer S . Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem. 2001; 70:341-67. DOI: 10.1146/annurev.biochem.70.1.341. View

Farce A, Renault N, Chavatte P . Structural insight into PPARgamma ligands binding. Curr Med Chem. 2009; 16(14):1768-89. DOI: 10.2174/092986709788186165. View

Giaginis C, Theocharis S, Tsantili-Kakoulidou A . Structural basis for the design of PPAR-gamma ligands: a survey on quantitative structure- activity relationships. Mini Rev Med Chem. 2009; 9(9):1075-83. DOI: 10.2174/138955709788922601. View

Pourcet B, Fruchart J, Staels B, Glineur C . Selective PPAR modulators, dual and pan PPAR agonists: multimodal drugs for the treatment of type 2 diabetes and atherosclerosis. Expert Opin Emerg Drugs. 2006; 11(3):379-401. DOI: 10.1517/14728214.11.3.379. View

Acton 3rd J, Black R, Jones A, Moller D, Colwell L, Doebber T . Benzoyl 2-methyl indoles as selective PPARgamma modulators. Bioorg Med Chem Lett. 2004; 15(2):357-62. DOI: 10.1016/j.bmcl.2004.10.068. View

Dixon S, Smondyrev A, Knoll E, Rao S, Shaw D, Friesner R . PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J Comput Aided Mol Des. 2006; 20(10-11):647-71. DOI: 10.1007/s10822-006-9087-6. View

Berger J, Moller D . The mechanisms of action of PPARs. Annu Rev Med. 2002; 53:409-35. DOI: 10.1146/annurev.med.53.082901.104018. View

10.

Montanari R, Saccoccia F, Scotti E, Crestani M, Godio C, Gilardi F . Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) 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(24):7768-76. DOI: 10.1021/jm800733h. View

11.

Furukawa A, Arita T, Satoh S, Wakabayashi K, Hayashi S, Matsui Y . Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives. Bioorg Med Chem Lett. 2010; 20(7):2095-8. DOI: 10.1016/j.bmcl.2010.02.073. View

12.

Jones D . Potential remains for PPAR-targeted drugs. Nat Rev Drug Discov. 2010; 9(9):668-9. DOI: 10.1038/nrd3271. View

13.

Willson T, Cobb J, Cowan D, Wiethe R, Correa I, Prakash S . The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem. 1996; 39(3):665-8. DOI: 10.1021/jm950395a. View

14.

Palau J, Romeu A . Horizontal gene transfer in glycosyl hydrolases inferred from codon usage in Escherichia coli and Bacillus subtilis. Mol Biol Evol. 1999; 16(9):1125-34. DOI: 10.1093/oxfordjournals.molbev.a026203. View

15.

Gelman L, Feige J, Desvergne B . Molecular basis of selective PPARgamma modulation for the treatment of Type 2 diabetes. Biochim Biophys Acta. 2007; 1771(8):1094-107. DOI: 10.1016/j.bbalip.2007.03.004. View

16.

Feldman P, Lambert M, Henke B . PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors?. Curr Top Med Chem. 2008; 8(9):728-49. DOI: 10.2174/156802608784535084. View

17.

Debenham S, Chan A, Lau F, Liu W, Wood H, Lemme K . Highly functionalized 7-azaindoles as selective PPAR gamma modulators. Bioorg Med Chem Lett. 2008; 18(17):4798-801. DOI: 10.1016/j.bmcl.2008.07.103. View

18.

Houtkooper R, Auwerx J . Obesity: New life for antidiabetic drugs. Nature. 2010; 466(7305):443-4. PMC: 3852809. DOI: 10.1038/466443a. View

19.

Salam N, Nuti R, Sherman W . Novel method for generating structure-based pharmacophores using energetic analysis. J Chem Inf Model. 2009; 49(10):2356-68. DOI: 10.1021/ci900212v. View

20.

Lehmann J, Moore L, Wilkison W, Willson T, Kliewer S . An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995; 270(22):12953-6. DOI: 10.1074/jbc.270.22.12953. View