Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Pharmacophore Identification for Peroxisome Proliferator-Activated Receptor Gamma Agonists

  • Sohn, Young-Sik (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU)) ;
  • Lee, Yu-No (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU)) ;
  • Park, Chan-In (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU)) ;
  • Hwang, S-Wan (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU)) ;
  • Kim, Song-Mi (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU)) ;
  • Baek, A-Young (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU)) ;
  • Son, Min-Ky (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU)) ;
  • Suh, Jung-Keun (Bio Computing Major, Korean German Institute of Technology) ;
  • Kim, Hyong-Ha (Division of Quality of Life, Center of Bioanalysis, Korea Research Institute of Standards and Science (KRISS)) ;
  • Lee, Keun-Woo (Division of Applied Life Science (BK21 Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU))
  • Received : 2010.10.08
  • Accepted : 2010.11.15
  • Published : 2011.01.20
Download PDF
⟨ Previous Next ⟩

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors and their activation induces regulation of fatty acid storage and glucose metabolism. Therefore, the $PPAR\gamma$ is a major target for the treatment of type 2 diabetes mellitus. In order to generate pharmacophore model, 1080 known agonists database was constructed and a training set was selected. The Hypo7, selected from 10 hypotheses, contains four features: three hydrogen-bond acceptors (HBA) and one general hydrophobic (HY). This pharmacophore model was validated by using 862 test set compounds with a correlation coefficient of 0.903 between actual and estimated activity. Secondly, CatScramble method was used to verify the model. Hence, the validated Hypo7 was utilized for searching new lead compounds over 238,819 and 54,620 chemical structures in NCI and Maybridge database, respectively. Then the leads were selected by screening based on the pharmacophore model, predictive activity, and Lipinski's rules. Candidates were obtained and subsequently the binding affinities to $PPAR\gamma$ were investigated by the molecular docking simulations. Finally the best two compounds were presented and would be useful to treat type 2 diabetes.

Keywords

References

  1. Gearing, K. L.; Gottlicher, M.; Teboul, M.; Widmark, E.; Gustafsson, J. A. Proc. Natl. Acad. Sci. USA 1993, 90, 1440. https://doi.org/10.1073/pnas.90.4.1440
  2. Issemann, I.; Prince, R. A.; Tugwood, J. D.; Green, S. J. Mol. Endocrinol. 1993, 11, 37. https://doi.org/10.1677/jme.0.0110037
  3. Desvergne, B.; Wahli, W. Endocr. Rev. 1999, 20, 649. https://doi.org/10.1210/er.20.5.649
  4. Bardot, O.; Aldridge, T. C.; Latruffe, N.; Green, S. Biochem. Biophys. Res. Commun. 1993, 192, 37. https://doi.org/10.1006/bbrc.1993.1378
  5. Feige, J. N.; Gelman, L.; Michalik, L.; Desvergne, B.; Wahli, W. Prog. Lipid. Res. 2006, 45, 120. https://doi.org/10.1016/j.plipres.2005.12.002
  6. Gurnell, M. Clin. Endocrinol. 2003, 59, 267. https://doi.org/10.1046/j.1365-2265.2003.01767.x
  7. Renaud, J. P.; Moras, D. Cell. Mol. Life. Sci. 2000, 57, 1748. https://doi.org/10.1007/PL00000656
  8. Voutsadakis, I. A. J. Cancer. Res. Clin. Oncol. 2007, 133, 917. https://doi.org/10.1007/s00432-007-0277-y
  9. Fajas, L.; Auboeuf, D.; Raspe, E.; Schoonjans, K.; Lefebvre, A. M.; Saladin, R.; Najib, J.; Laville, M,; Fruchart, J. C.; Deeb, S.; Vidal-Puig, A.; Flier, J.; Briggs, M. R.; Staels, B.; Vidal, H.; Auwerx, J. J. Biol. Chem. 1997, 272, 18779. https://doi.org/10.1074/jbc.272.30.18779
  10. Chen, Y.; Jimenez, A. R.; Medh, J. D. Biochim. Biophys. Acta 2006, 1759, 32. https://doi.org/10.1016/j.bbaexp.2006.01.005
  11. Elbrecht, A.; Chen, Y.; Cullinan, C. A.; Hayes, N.; Leibowitz, M.; Moller, D. E.; Berger, J. Biochem. Biophys. Res. Commun. 1996, 224, 431. https://doi.org/10.1006/bbrc.1996.1044
  12. Hara, K.; Okada, T.; Tobe, K.; Yasuda, K.; Mori, Y.; Kadowaki, H.; Hagura, R.; Akanuma, Y.; Kimura, S.; Ito, C.; Kadowaki, T. Biochem. Biophys. Res. Commun. 2000, 271, 212. https://doi.org/10.1006/bbrc.2000.2605
  13. Nomura, M.; Tanase, T.; Ide, T.; Tsunoda, M.; Suzuki, M.; Uchiki, H.; Murakami, K.; Miyachi, H. J. Med. Chem. 2003, 46, 3581. https://doi.org/10.1021/jm0205144
  14. Koyama, H.; Boueres, J. K.; Han, W.; Metzger, E. J.; Bergman, J. P.; Gratale, D. F.; Miller, D. J.; Tolman, R. L.; MacNaul, K. L.; Berger, J. P.; Doebber, T. W.; Leung, K.; Moller, D. E.; Heck, J. V.; Sahoo, S. P. Bioorg. Med. Chem. Lett. 2003, 13, 1801. https://doi.org/10.1016/S0960-894X(03)00257-9
  15. Koyama, H.; Boueres, J. K.; Miller, D. J.; Berger, J. P.; MacNaul, K. L.; Wang, P. R.; Ippolito, M. C.; Wright, S. D.; Agrawal, A. K.; Moller, D. E.; Sahoo, S. P. Bioorg. Med. Chem. Lett. 2005, 15, 3347. https://doi.org/10.1016/j.bmcl.2005.05.028
  16. Kim, N. J.; Lee, K. O.; Koo, B. W.; Li, F.; Yoo, J. K.; Park, H. J.; Min, K. H.; Lim, J. I.; Kim, M. K.; Kim, J. K.; Suh, Y. G. Bioorg. Med. Chem. Lett. 2007, 17, 3595. https://doi.org/10.1016/j.bmcl.2007.04.057
  17. Sauerberg, P.; Bury, P. S.; Mogensen, J. P.; Deussen, H. J.; Pettersson, I.; Fleckner, J.; Nehlin, J.; Frederiksen, K. S.; Albrektsen, T.; Din, N.; Svensson, L. A.; Ynddal, L.; Wulff, E. M.; Jeppesen, L. J. Med. Chem. 2003, 46, 4883. https://doi.org/10.1021/jm0309046
  18. Casimiro-Garcia, A.; Bigge, C. F.; Davis, J. A.; Padalino, T.; Pulaski, J.; Ohren, J. F.; McConnell, P.; Kane, C. D.; Royer, L. J.; Stevens, K. A.; Auerbach, B. J.; Collard, W. T.; McGregor, C.; Fakhoury, S. A.; Schaum, R. P.; Zhou, H. Bioorg. Med. Chem. 2008, 16, 4883. https://doi.org/10.1016/j.bmc.2008.03.043
  19. Mahindroo, N.; Wang, C. C.; Liao, C. C.; Huang, C. F.; Lu, I. L.; Lien, T. W.; Peng, Y. H.; Huang, W. J.; Lin, Y. T.; Hsu, M. C.; Lin, C. H.; Tsai, C. H.; Hsu, J. T.; Chen, X.; Lyu, P. C.; Chao, Y. S.; Wu, S. Y.; Hsieh, H. P. J. Med. Chem. 2006, 49, 1212. https://doi.org/10.1021/jm0510373
  20. Mahindroo, N.; Huang, C. F.; Peng, Y. H.; Wang, C. C.; Liao, C. C.; Lien, T. W.; Chittimalla, S. K.; Huang, W. J.; Chai, C. H.; Prakash, E.; Chen, C. P.; Hsu, T. A.; Peng, C. H.; Lu, I. L.; Lee, L. H.; Chang, Y. W.; Chen, W. C.; Chou, Y. C.; Chen, C. T.; Goparaju, C. M.; Chen, Y. S.; Lan, S. J.; Yu, M. C.; Chen, X.; Chao, Y. S.; Wu, S. Y.; Hsieh, H. P. J. Med. Chem. 2005, 48, 8194. https://doi.org/10.1021/jm0506930
  21. Koyama, H.; Miller, D. J.; Boueres, J. K.; Desai, R. C.; Jones, A. B.; Berger, J. P.; MacNaul, K. L.; Kelly, L. J.; Doebber, T. W.; Wu, M. S.; Zhou, G.; Wang, P. R.; Ippolito, M. C.; Chao, Y. S.; Agrawal, A. K.; Franklin, R.; Heck, J. V.; Wright, S. D.; Moller, D. E.; Sahoo, S. P. J. Med. Chem. 2004, 47, 3255. https://doi.org/10.1021/jm030621d
  22. Liu, K.; Xu, L.; Berger, J. P.; Macnaul, K. L.; Zhou, G.; Doebber, T. W.; Forrest, M. J.; Moller, D. E.; Jones, A. B. J. Med. Chem. 2005, 48, 2262. https://doi.org/10.1021/jm048993p
  23. Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. J. Med. Chem. 2000, 43, 527. https://doi.org/10.1021/jm990554g
  24. Li, Z.; Liao, C.; Ko, B. C.; Shan, S.; Tong, E. H.; Yin, Z.; Pan, D.; Wong, V. K.; Shi, L.; Ning. Z. Q.; Hu, W.; Zhou, J.; Chung, S. S.; Lu, X. P. Bioorg. Med. Chem. Lett. 2004, 14, 3507. https://doi.org/10.1016/j.bmcl.2004.04.053
  25. Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Pettersson, I.; Fleckner, J.; Nehlin, J.; Frederiksen, K. S.; Albrektsen, T.; Din, N.; Mortensen, S. B.; Svensson, L. A.; Wassermann, K.; Wulff, E.M.; Ynddal, L.; Sauerberg, P. Bioorg. Med. Chem. Lett. 2003, 13, 257. https://doi.org/10.1016/S0960-894X(02)00881-8
  26. Thor, M.; Beierlein, K.; Dykes, G.; Gustavsson, A. L.; Heidrich, J.; Jendeberg, L.; Lindqvist, B.; Pegurier, C.; Roussel, P.; Slater, M.; Svensson, S.; Sydow-Backman, M.; Thornstrom, U.; Uppenberg, J. Bioorg. Med. Chem. Lett. 2002, 12, 3565. https://doi.org/10.1016/S0960-894X(02)00791-6
  27. Sauerberg, P.; Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Fleckner, J.; Olsen, G. S.; Jeppesen, C. B.; Wulff, E. M.; Pihera, P.; Havranek, M.; Polivka, Z.; Pettersson, I. Bioorg. Med. Chem. Lett. 2007, 17, 3198. https://doi.org/10.1016/j.bmcl.2007.03.015
  28. Desai, R. C.; Gratale, D. F.; Han, W.; Koyama, H.; Metzger, E.; Lombardo, V. K.; MacNaul, K. L.; Doebber, T. W.; Berger, J. P.; Leung, K.; Franklin, R.; Moller, D. E.; Heck, J. V.; Sahoo, S. P. Bioorg. Med. Chem. Lett. 2003, 13, 3541. https://doi.org/10.1016/S0960-894X(03)00785-6
  29. Caijo, F.; Mosset, P.; Gree, R.; Audinot-Bouchez, V.; Boutin, J.; Renard, P.; Caignard, D. H.; Dacquet, C. Bioorg. Med. Chem. Lett. 2005, 15, 4421. https://doi.org/10.1016/j.bmcl.2005.07.049
  30. Han, H. O.; Kim, S. H.; Kim, K. H.; Hur, G. C.; Yim, H. J.; Chung, H. K.; Woo, S. H.; Koo, K. D.; Lee, C. S.; Koh, J. S.; Kim, G. T. Bioorg. Med. Chem. Lett. 2007, 17, 937. https://doi.org/10.1016/j.bmcl.2006.11.050
  31. Bharatham, K.; Bharatham, N.; Lee, K. W. Arch. Pharm. Res. 2007, 30, 533. https://doi.org/10.1007/BF02977644
  32. Lee, Y.; Bharatham, N.; Bharatham, K.; Lee, K. W. Bull. Korean. Chem. Soc. 2007, 28, 561. https://doi.org/10.5012/bkcs.2007.28.4.561
  33. CATALYST 4.10; Accelrys, Inc., San Diego, CA, 2005, http://www.accelrys.com.
  34. Du, L. P.; Li, M. Y.; Tsai, K. C.; You, Q. D.; Xia, L. Biochem. Biophys. Res. Commun. 2007, 322, 677.
  35. Bharatham, N.; Bharatham, K.; Lee, K. W. J. Mol. Graph. Model. 2007, 25, 813. https://doi.org/10.1016/j.jmgm.2006.08.002
  36. Bharatham, N.; Bharatham, K.; Lee, K. W. Bull. Korean. Chem. Soc. 2007, 28, 200. https://doi.org/10.5012/bkcs.2007.28.2.200
  37. Tetko, I. V. Mini. Rev. Med. Chem. 2003, 3, 809. https://doi.org/10.2174/1389557033487638
  38. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug. Deliv. Rev. 2001, 46, 3. https://doi.org/10.1016/S0169-409X(00)00129-0
  39. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727. https://doi.org/10.1006/jmbi.1996.0897

Cited by

  1. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands vol.29, pp.5, 2015, https://doi.org/10.1007/s10822-015-9831-x
  2. analysis on 3T3-L1 cell line vol.41, pp.15, 2015, https://doi.org/10.1080/08927022.2014.970188
  3. Therapeutic potential of compound K as an IKK inhibitor with implications for osteoarthritis prevention: an in silico and in vitro study vol.52, pp.9, 2016, https://doi.org/10.1007/s11626-016-0062-9
  4. Structural investigation of ginsenoside Rf with PPARγ major transcriptional factor of adipogenesis and its impact on adipocyte vol.39, pp.2, 2011, https://doi.org/10.1016/j.jgr.2014.10.002
  5. Ginsenoside Rf inhibits cyclooxygenase-2 induction via peroxisome proliferator-activated receptor gamma in A549 cells vol.43, pp.2, 2011, https://doi.org/10.1016/j.jgr.2018.11.007